Cystoid Macular Edema: Medical and Surgical Management [1st ed. 2017] 3319397648, 9783319397641

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Cystoid Macular Edema Medical and Surgical Management Shlomit Schaal Henry J. Kaplan Editors

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Cystoid Macular Edema

Shlomit Schaal • Henry J. Kaplan Editors

Cystoid Macular Edema Medical and Surgical Management

Editors Shlomit Schaal, MD, PhD Professor and Chair Department of Ophthalmology and Visual Sciences University of Massachusetts School of Medicine Worcester, MA USA

Henry J. Kaplan, MD Evans Professor and Chair of Ophthalmology and Visual Sciences University of Louisville Louisville, KY USA

ISBN 978-3-319-39764-1 ISBN 978-3-319-39766-5 DOI 10.1007/978-3-319-39766-5

(eBook)

Library of Congress Control Number: 2016958301 © Springer International Publishing Switzerland 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is Gewerbestrasse 11, 6330 Cham, Switzerland

This book is dedicated to my beloved mentor, Dr. Henry J. Kaplan, who is recognized around the world as one of the brightest and sharpest minds in retina and uveitis. For his wise guidance, admirable leadership, endless inspiration, and persistent support have produced generations of outstanding clinicians and scientists. On behalf of all your grateful students, Shlomit Schaal, M.D., Ph.D.

Acknowledgment

The authors would like to sincerely thank all the world renowned contributors to this book, who spent time and effort to write high quality state-of-the-art informative chapters. Special thanks to Dr. Shivani Reddy, who helped proof reading the book. This book was supported by an unrestricted institutional grant from Research to Prevent Blindness.

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Contents

Part I

Pathophysiology and Diagnosis of CME

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Shlomit Schaal and Henry J. Kaplan

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Mechanisms of Macular Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Alejandra Daruich-Matet, Alexandre Matet, and Francine Behar-Cohen

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Diagnosis of Cystoid Macular Edema: Imaging . . . . . . . . . . . . . . . . . . 27 Dilraj S. Grewal and Glenn J. Jaffe

Part II

Medical Management of CME

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Medical Management of CME Associated with Uveitis . . . . . . . . . . . . 59 Sarah M. Escott and Debra A. Goldstein

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Medical Management of CME Associated with Diabetes . . . . . . . . . . . 77 Reid Turner and Lucian Del Priore

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Management of Macular Edema in Vitreo-Maculopathies . . . . . . . . . . 91 Matin Khoshnevis and J. Sebag

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Medical Management of CME Associated with Retinal Vascular Occlusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Wolf Buehl and Ursula M. Schmidt-Erfurth

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Cystoid Macular Edema in Retained Lens Fragments After Cataract Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Motasem Al-latayfeh

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Part III

Surgical Management of CME

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Surgical Management of Macular Edema Associated with Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Alexander L. Grigalunas and Pauline T. Merrill

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Surgical Management of Diabetic Macular Edema . . . . . . . . . . . . . . . 163 Katherine E. Talcott and Dean Eliott

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Surgical Management of CME Associated with Vitreoretinal Interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Mauricio Maia, Juliana Bottós, Javier Elizalde, Emerson Badaro, and J. Fernando Arevalo

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Surgical Management of Cystoid Macular Edema Associated with Retinal Vascular Occlusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Ahmet M. Hondur and Tongalp H. Tezel

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Surgical Management of Vitreous Retained Lens Fragments During or Following Phacoemulsification Surgery . . . . . 215 Pedro Amat-Peral, Jorge L. Alió y Sanz, and Francisco L. Lugo-Quintás

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Conclusion and Outlook for the Future . . . . . . . . . . . . . . . . . . . . . . . . 233 Shlomit Schaal and Henry J. Kaplan

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

Contributors

Motasem Al-latayfeh, MD Department of Opthalmology, Hashemite University, Zarqa, Jordan Jorge L. Alió y Sanz, MD, PhD, FEBO Cataract and Refractive Surgery Unit, Vissum, Instituto Oftalmológico de Alicante, Alicante, Spain Miguel Hernández University, Alicante, Spain Pedro Amat-Peral, MD, PhD, FEBO Vitreous-Retina Unit, Vissum, Instituto Oftalmológico de Alicante, Alicante, Spain J. Fernando Arevalo, MD, FACS Retina Division, Department of Ophthalmology, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Emerson Badaro, MD Vitreoretinal Sector, Department of Ophthalmology, Federal University of São Paulo, UNIFESP, Brazil, São Paulo, SP, Brazil Francine Behar-Cohen, MD, PhD Department of Ophthalmology, University of Lausanne Jules Gonin Eye Hospital, Lausanne, Switzerland Inserm U1138, Centre de Recherche des Cordeliers, Paris, France Juliana Bottós, MD Vitreoretinal Sector, Department of Ophthalmology, Federal University of São Paulo, UNIFESP, Brazil, São Paulo, SP, Brazil Wolf Buehl, MD Department of Ophthalmology, Medical University of Vienna, Vienna, Austria Alejandra Daruich-Matet, MD, MS Department of Ophthalmology, University of Lausanne Jules Gonin Eye Hospital, Lausanne, Switzerland Lucian V. Del Priore, MD, PhD Department of Ophthalmology, Yale University School of Medicine, New Haven, CT, USA Dean Eliott, MD Retina Service, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, USA xi

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Contributors

Javier Elizalde, MD Vitreoretinal Surgery Unit, Institut Barraquer, Barcelona, Spain Sarah M. Escott, MD Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Debra A. Goldstein, MD Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Dilraj S. Grewal, MD Duke Eye Center, Durham, NC, USA Alexander L. Grigalunas, MD Department of Ophthalmology, Rush University Medical Center, Chicago, IL, USA Ahmet M. Hondur, MD Department of Ophthalmology, School of Medicine, Gazi University, Ankara, Turkey Glenn J. Jaffe, MD Duke Eye Center, Durham, NC, USA Henry J. Kaplan, MD Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY, USA Matin Khoshnevis, MD VMR Institute for Vitreous Macula Retina, Huntington Beach, CA, USA Temple University, Department of Ophthalmology, Philadelphia, PA, USA Francisco L. Lugo-Quintás, MD, PhD Vitreous-Retina Unit, Vissum, Instituto Oftalmológico de Alicante, Alicante, Spain Mauricio Maia, MD, PhD Vitreoretinal Surgery Unit, Universidade Federal de Sao Paulo, Brazilian Institute of Fight Against Blindness, Assis/Presidente Prudente, SP, Brazil Alexandre Matet, MD, MSc Department of Ophthalmology, University of Lausanne Jules Gonin Eye Hospital, Lausanne, Switzerland Pauline T. Merrill, MD Department of Ophthalmology, Rush University Medical Center, Chicago, IL, USA Shlomit Schaal, MD, PhD Department of Ophthalmology and Visual Sciences, University of Massachusetts School of Medicine, Amherst, MA, USA Ursula M. Schmidt-Erfurth, MD Department of Ophthalmology, Medical University of Vienna, Vienna, Austria J. Sebag, MD, FACS, FRCOphth, FARVO VMR Institute for Vitreous Macula Retina, Huntington Beach, CA, USA Katherine E. Talcott, MD Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Harvard Medical School, Boston, MA, USA

Contributors

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Tongalp H. Tezel, MD Department of Ophthalmology, Columbia University College of Physicians and Surgeons, Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY, USA Reid Turner, MD Department of Ophthalmology, Medical University of South Carolina, Storm Eye Institute, Charleston, SC, USA

Part I

Pathophysiology and Diagnosis of CME

Chapter 1

Introduction Shlomit Schaal and Henry J. Kaplan

Macular edema is defined as swelling of the layers of the neurosensory retina within the macula. Although the classic presentation of macular edema is termed “cystoid macular edema” (CME), which represents the collection of excess fluid in “cysts” within the neurosensory retina, it is more broadly defined as extracellular accumulation of fluid within the outer plexiform layer of the retina. Thus, CME should be referred to as a subtype of macular edema with specific characteristics on imaging studies (e.g., fluorescein angiography and optical coherence tomography [OCT]). The most common clinical manifestation of macular edema is a reduction in central visual acuity. However, it is now recognized that macular edema may exist without impairing visual acuity but detectable on sophisticated retinal imaging. Thus, reliance on visual acuity to exclude the presence of macular edema is not sufficient, nor is it appropriate to rely on vision to suggest resolution of macular edema in response to treatment. Other clinical manifestations of macular edema include micropsia, in which objects appear smaller than they really are, as well as metamorphopsia. Although macular edema is reversible through both medical and surgical intervention, the development of chronic macular edema may eventually result in irreversible photoreceptor damage with a constant central scotoma. Other functional indications of the presence of macular edema include decreased reading speed, as well as reduced contrast sensitivity.

S. Schaal, MD, PhD Professor and Chair, Department of Ophthalmology and Visual Sciences, University of Massachusetts School of Medicine, Amherst, MA, USA e-mail: [email protected] H.J. Kaplan, MD ( ) Evans Professor and Chair of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY, USA e-mail: [email protected] © Springer International Publishing Switzerland 2017 S. Schaal, H.J. Kaplan (eds.), Cystoid Macular Edema, DOI 10.1007/978-3-319-39766-5_1

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The pathogenesis and etiology of macular edema is rather complex. Although the hallmark of this complication of many different diseases is the accumulation of intraretinal fluid, macular edema can occur as a result of multiple and diverse mechanisms: the breakdown of inner blood-retinal barrier (e.g., endothelial cell tight junctions), breakdown of the outer retinal barrier (e.g., tight junctions between RPE cells), and/or interference with the normal egress of retinal fluid by cells within the neurosensory retina (e.g., Mueller cell dysfunction or retinal pigment epithelium (RPE) dysfunction). Macular edema is the leading cause of central vision loss that accompanies many systemic diseases, including diabetes mellitus and systemic inflammatory conditions associated with uveitis. However, it is also a complication of many other retinal diseases including retinal vascular diseases (choroidal neovascularization in age-related macular degeneration, hypertensive retinopathy, central retinal vein occlusion, branch retinal vein occlusion), uveal inflammation (e.g., HLA-B27 acute anterior uveitis, pars planitis, birdshot chorioretinopathy), tractional forces on the retina (e.g., epiretinal membrane formation, vitreomacular traction syndrome), retinal dystrophies (e.g., retinitis pigmentosa, Goldman-Favre syndrome, juvenile x-linked retinoschisis), intraocular tumors (e.g., choroidal hemangioma, choroidal melanoma, retinal hemangioma), adverse effect of medications (e.g., niacin, tamoxifen), and idiopathic diseases. Prior to the development of modern imaging techniques, funduscopy was the sole method to detect macular edema, in particular CME. The introduction of fluorescein angiography was a major imaging advancement that revolutionized our appreciation and quantification of CME, as well as the mechanisms leading to the development of macular edema. The more recent development of autofluorescence imaging and in particular the widespread use of spectral domain OCT have allowed us to obtain much greater insight into the anatomical alterations caused by macular edema. The application of these imaging technologies has allowed us to identify three different patterns of macular edema – (1) CME, characterized by clearly defined intraretinal cystic spaces within the neurosensory retina; (2) diffuse macular edema, characterized by increased retinal thickness and disturbance of the layered retinal structure; and (3) serous retinal detachment, characterized by separation of the neurosensory retina from the underlying RPE. It is also now apparent that the absence of macular edema on fluorescein angiography does not necessarily correlate with the results of other imaging techniques. Thus, multimodal imaging provides us with the most sophisticated tools to determine and document the presence of macular edema. Since macular edema is associated with so many different causes, the response of macular edema to therapy is obviously quite variable. Multiple medications, as well as surgical intervention, have been used with reported success and CME resolution in several diseases. It is clear that the underlying pathogenesis of the disease must be clearly identified to obtain the best therapeutic response to intervention. However, it is recognized that response to treatment may vary between patients depending upon personal genetic makeup and exposure to environmental factors.

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Since macular edema is a major cause of visual disability, we have been fortunate, as editors of this book, to have enlisted the expertise of several internationally respected clinicians and scientists to address three major areas in this text: Part I – Pathophysiology and Diagnosis of CME Part II – Medical Management of CME Part III – Surgical Management of CME It is our intent to provide a contemporary update into the cause of this major visual complication to allow a more accurate diagnosis, as well as therapeutic intervention for the reversal of this disease complication. The many advances that have been made in both diagnosis and in the understanding of the underlying pathophysiology of this disease have resulted in the development of novel medications that prevent the permanent loss of central vision. We are indebted to the many scholarly contributors to this text and personally thank them for their excellent contributions.

Chapter 2

Mechanisms of Macular Edema Alejandra Daruich-Matet, Alexandre Matet, and Francine Behar-Cohen

Introduction Macular edema (ME) can be defined as a collection of fluid within and/or under the retina in the macular region. ME can be identified by a diffuse increase in retinal thickness, the formation of intraretinal cysts, and the accumulation of subretinal fluid (Fig. 1). Whether distinct pathogenic mechanisms induce different types of fluid accumulation is unclear. ME can manifest in nearly all retinal diseases at various phases of their development. Most frequently ME is associated with ischemia/hypoxia and/or inflammation. Systemic factors such as increased blood pressure (hypertension) or reduced plasma oncotic pressure (hypoalbuminemia) can aggravate ME. In physiologic conditions, active mechanisms permanently maintain the retina in a transparent and relatively dehydrated state. Fluid can enter in the retina from the vitreous, from the retinal vessels, and from the subretinal space through the retinal pigment epithelium (RPE). Fluid entry from the circulation into the retina is controlled by the inner blood-retinal barrier, formed by endothelial tight junctions, pericytes, astrocytes, and retinal Müller glia (RMG) [1], and by the outer retinal barrier, formed by the tight junction of the retinal pigment epithelium (RPE) [2]. Fluid exit through the RPE is ensured by active ion and water channels

A. Daruich-Matet, MD, MS • A. Matet, MD, MSc Department of Ophthalmology, University of Lausanne Jules Gonin Eye Hospital, 15 avenue de France, Lausanne 1004, Switzerland F. Behar-Cohen, MD, PhD (*) Department of Ophthalmology, University of Lausanne Jules Gonin Eye Hospital, 15 avenue de France, Lausanne 1004, Switzerland Inserm U1138, Centre de Recherche des Cordeliers, 15 rue de l’Ecole de Medecine, Paris 75006, France e-mail: [email protected] © Springer International Publishing Switzerland 2017 S. Schaal, H.J. Kaplan (eds.), Cystoid Macular Edema, DOI 10.1007/978-3-319-39766-5_2

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Fig. 1  Macular edema: fluid accumulation within and/or under the retina. Spectral-domain optical coherence tomography (SD-OCT) section (a) and histology (b) of a healthy human retina. Note the different retinal layers from the choroid to the vitreous cavity: RPE retinal pigment epithelium, ELM external limiting membrane, IS/OS photoreceptors inner segment/outer segment junction, ONL outer nuclear layer, OPL outer plexiform layer, INL inner nuclear layer, IPL inner plexiform layer, GCL ganglion cell layer, ILM internal limiting membrane, RNFL retinal nerve fiber layer. Diabetic macular edema imaged on SD-OCT (c) and histology of a human macula presenting macular edema (d), diplaying an increase in retinal thickness (red arrows), the formation of intraretinal cysts (green stars), and the accumulation of subretinal fluid (short red arrows)

[3]. It is facilitated by the oncotic pressure-driven flow. Numerous ionic transports are strictly regulated in RPE cells and contribute to the outward flux from the subretinal space toward the choroid. RMG cells also play an important role in ion and water drainage from the inner retina toward the retinal vessels (Fig. 2). In physiologic conditions, potassium transport is associated with water drainage through Kir (inwardly rectifying potassium channels) and aquaporin (AQP) channels that are both expressed in RMG cells [4, 5]. The exact molecular partners of ion and water coupling are only partially known in the retina. It is accepted that Kir4.1 and AQP4, located in RMG cells around retinal vessels and in RMG end feet, are key players in this balance (Fig. 2). Moreover, tight-like junctions recently identified at the external limiting membrane (ELM) between RMG and photoreceptors control the passive movement of fluid in the outer retina (Fig. 3). Altogether, these different mechanisms act in a synchronized manner to control the retinal thickness. The density of RMG cells is higher in the macula than in any other region of the retina. In addition, their morphology also differs, with a perifoveal portion orientated radially and almost parallel to the frontal plane [6, 7] which suggests that RMG cells exhibit different functions in the macula than in the periphery. Whether ion and water transport mechanisms also present specific features in the macula should be explored and could contribute to explain the specific location of edema in the macula.

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Fig. 2 (a) Schematic representation of a retinal Müller glial cell illustrating its roles in ion and water drainage from the inner retina toward the retinal vessels. Potassium transport is associated with water drainage through Kir4.1 (inwardly rectifying potassium channels) and AQP4 (aquaporin) channels, both located close to the interface of the retinal Müller glial cell with retinal vessels and in retinal Müller glial end feet at the level of the internal limiting membrane. (b) Schematic representation of RPE cells illustrating the drainage of water and electrolytes from the subretinal space to the choroid via paracellular diffusion, facilitated diffusion, and active transport

Mechanisms Leading to ME ME results from an imbalance between fluid entry and fluid exit leading to an accumulation of fluid within and/or under the retina and in the extracellular and/or in the intracellular media (Fig. 4). The pathogenic mechanisms of ME can be classified as “vasogenic,” which reflects a vascular leakage with a volumetric influx of extracellular fluid or “cytotoxic” which reflects cell swelling induced by a volumetric increase in intracellular fluid.

 echanisms Leading to Increased Retinal Fluid Entry or M “Vasogenic” Mechanisms Starling Equation The Starling equation represents the movements of fluid in and out capillary vessels. It depends on capillary filtration, hydrostatic, and oncotic pressure – i.e., Starling forces.

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Fig. 3  The structure of the external limiting membrane and distribution of retinal Müller glial cells. (a) Spectral-domain optical coherence tomography of healthy macula highlighting the hyperreflective signal attributed to the external limiting membrane. (b) Tight-like junctions and adherens junctions are found at the level of the external limiting membrane between retinal Müller glia and photoreceptors and rely on specialized molecular families including zonula occludens-1. Macular flat mounts from healthy monkeys (Macaca fascicularis) after immunostaining of glutamine synthetase (c, red), marker of Müller cells, zonula occludens-1 (d, green), and fusion of both fluorescence images (e). The colocalization of both markers (appearing yellow in e) indicates a close relationship between tight junctions and retinal Müller glial cells

The Starling equation reads as follows: where:

J v = K f ([ Pc - Pi ] - s [p c - p i ])

Jν is the net fluid movement between compartments Pc is the capillary hydrostatic pressure Pi is the interstitial hydrostatic pressure πc is the capillary oncotic pressure πi is the interstitial oncotic pressure Kf is the filtration coefficient – a proportionality constant σ is the reflection coefficient



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Fig. 4  Mechanisms of macular edema. Macular edema results from an imbalance between fluid entry and fluid exit leading to an abnormal accumulation of fluid within and/or under the retina (*the contribution of the vitreous on the retinal fluid entry is limited)

In conditions such as inflammation and elevated intracapillary pressure, the forces and membrane parameters governing transendothelial flux enhance filtration and increase the interstitial accumulation of albumin. The increased oncotic pressure in the neuroretina reduces fluid absorption and leads to retinal edema. Rupture of Retinal Barriers Barrier properties of retinal blood vessels and the RPE are due mainly to the presence of complex tight junction networks between cells. Tight junction and adherens junctions are integral membrane structures connected to the actin cytoskeleton via different adaptor molecules. Tight junctions are constituted by occludins, claudins (particularly claudin 5), and junction-associated molecules (JAM) connected to PDZ domain-containing proteins (among which is zonula occludens-1) and associated with an atypical protein kinase responsible for the tightly regulated phosphorylation of junction proteins (e.g., protein kinase C zeta, PKCζ). Junction proteins are transmembrane adhesive molecules closely linked to the cytoskeleton and with polarization proteins in the RPE. Tight junction destabilization can result from alteration of phosphorylation enzyme activity (e.g., PKCζ in diabetes), reduction of tight junction protein expression (e.g., occludin in diabetes), alteration of the cytoskeleton (e.g., secondary to oxidative damage or activation of RhoA/ROCK1 pathway), calcium dynamics [8], cell loss or severe cell damage (e.g., in case of severe inflammatory processes), and degradation of tight junction molecules by activation of proteases [9]. During inflammation, the exact molecular mechanisms that lead to tight junction disruption remain imperfectly understood. The cross talk between microglia and endothelial cells could contribute to tight junction expression regulation [10], while actin-binding molecules could also control vascular permeability

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via various signaling mechanisms such as activation of small GTPases [11]. Several extracellular signals could also intervene through signaling pathways leading to phosphorylation of actin and/or junction proteins, leading to their displacement from the membrane to other subcellular compartments. Mechanical stress can also contribute to tight junction rupture as observed in the RPE submitted to chronic pressure secondary to vascular or melanocytic tumors in the choroid or to choroidal vasodilation in central serous chorioretinopathy. Soluble mediators inducing vascular and/or RPE permeability include cytokines, such us monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukins (IL-1b, IL-8, IL-6), vascular endothelial growth factor (VEGF) family members, acute phase proteins, enzymes, plasma activation systems (contact system, complement factor system, coagulation factors, fibrinolysis factors), arachidonic acid metabolites, biogenic or vasoactive amines (histamine, serotonin), eosinophil granular proteins, neuropeptides, oxygen free radicals, and nitric oxide. Vascular Abnormalities Associated with Enhanced Permeability Besides alteration of the tight and adherens junction complexes, other abnormal vascular changes can lead to increased fluid entry, visualized by “leakage” of dye during fluorescein angiography. This is the case for retinal neovascularization proliferating at the surface of the retina, with immature and low parietal stabilization, aneurysmal dilation of retinal capillaries (leaky microaneurysms in diabetic retinopathy), and vascular telangiectasia associated with intense protein leakage (as observed in Type 1 idiopathic macular telangiectasia and Coats’ disease). Factors potentially increasing the vascular permeability include lower pericyte coverage, hemodynamic changes with focal occlusions and secondary endothelial alterations, and elevation of the intravascular pressure. Factors inducing vascular abnormalization include ischemia through hypoxia-­ inducible factor 1-alpha (HIF-1a), VEGFA and placental growth factor (PGF), and oxidative stress through advanced glycation end products (AGE). In certain disorders, such as Type 2 idiopathic macular telangiectasia, they remain unknown. The role of microglial cells and RMG cells is now considered as important players in the development of retinal vascular diseases [12]. RPE Dysfunction RPE dysfunction can contribute to fluid entry from the choroid into the subretinal space. This enhanced fluid entry does not strictly belong to the classical vasogenic mechanisms. Indeed, the RPE transports water from the subretinal space into the choroid without rupture of the RPE tight junctions. The important RPE absorption capacity is particularly obvious in case of retinal detachment. RPE transport of Cl− and K+ is thought to drive transepithelial water transport. But in physiologic basal

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conditions, the Cl− conductance is up to 70% of the total basolateral conductance. The transport rate of water through RPE is estimated between 1.4 and 11 μl/cm2/h [13]. Fluid absorption involves complex mechanisms operating in the apical and basolateral membranes of the RPE cells that involve Cl− transport, Na+/K+-ATPase activity, and Ca2+-activated, volume-activated, and/or cAMP-activated ion channels. These mechanisms are differentially regulated under light or dark conditions and are influenced by the circadian rhythm. Ion absorption in the RPE is accompanied by water transport through aquaporins [5, 14–16]. Calcium channels in the RPE were shown to regulate VEGF expression, suggesting a potential link between RPE ion transport and VEGF-induced permeability [17]. In pathological conditions such as diabetic retinopathy, changes in aquaporin expression were shown at the level of RPE [18]. Subretinal fluid accumulation resulting from alteration of fluid and ion transport across the RPE has also been suggested in central serous chorioretinopathy (Fig. 10a), but whether such changes per se are able to induce subretinal fluid in the absence of RPE barrier disruption has not been demonstrated.

Fig. 5 (a) Normal retina; (b) Diabetic retina. Retinal Müller glial cells in normal and diabetic retina. Retinal Müller glial cells drive water flux in and out the vessels through AQP4 and Kir4.1 channels, which are altered in pathologic states provoking macular edema. In the diabetic retina, the drainage capability of the retinal Müller glial cell is overwhelmed, and AQP4 and Kir4.1 are displaced toward the outer portion of the retinal Müller glial cell. Additional channels (AQP1 and AQP9) are also expressed at the cell surface. As a consequence of macular edema, glutamate accumulates, and its cellular toxicity contributes to the persistence of the macular edema

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 echanisms Leading to Reduced Retinal Fluid Exit or M “Cytotoxic” Mechanisms: Retinal Müller Glia Dysfunction RMG drainage functions are altered in almost all retinal diseases associated with ischemia and inflammation, as well as in chronic hyperglycemia [19]. RMG cells play a central role in the hydro-ionic balance in the retina, absorbing water from the retinal tissue by water transport coupled to the potassium clearance function. Kir4.1 channels are localized in the RMG cells’ membrane around the vessels in physiologic conditions but undergo a change in localization and/or levels of expression in pathologic conditions. This leads to potassium excess within RMG cells, subsequent cellular swelling, and enhanced potassium levels in the extracellular milieu with increased osmotic pressure. Retinal cysts can at least in part result from RMG swelling and necrotic death [4, 20]. RMG cells also drive water flux in and out the vessels through AQP4 channels, which are also altered in pathologic states (Fig. 5). There are other evidences of the central role of RMG cells in ME formation such as pharmacotoxic ME induced by chemotherapy drugs, which presents with silent ME on fluorescein angiography. In these cases, drugs damaging the cytoskeleton can lead to pure cytotoxic edema without any clinically detectable vasogenic component. Interestingly, studies have shown that potassium conductance decreases in the aging human retina favoring ME in elderly patients [21].

Mechanical Tractions Any tractional force exerted at the vitreoretinal interface and/or under the retina can cause or aggravate ME (Fig. 6). Three hypotheses may explain the mechanical formation of ME: the deformations caused by traction on Müller cells, with subsequent metabolic impairment; the deformation of vessels with subsequent leakage from altered vascular walls; and the decreased interstitial hydrostatic pressure creating water, ion, and protein influx within the neuroretinal tissue. In physiologic conditions, vitreous collagen fibers distribute tractional forces evenly to the vitreoretinal interface, where they are intertwined with RMG cell end feet at the internal limiting membrane (ILM). In case of vitreomacular traction exerted after partial vitreous detachment, the same tractional forces are applied locally to fewer RMG cells. This may lead to chronic RMG cell irritation and local release of inflammatory mediators, which in turn may facilitate vascular leakage [22]. The same mechanical process may account for vascular alterations, particularly because vessels are located in the inner retinal layers. Finally, persistent tractional forces applied to the vitreoretinal interface may lead to a decreased interstitial hydrostatic pressure within the neuroretinal tissue. By diminishing the interstitial pressure term in Starling’s law, this traction results in an increased fluid influx from the vascular compartment [23, 24]. These processes probably occur simultaneously in the pathophysiology of mechanical ME. Epiretinal membranes, macular pucker, vitreomacular traction due to abnormal vitreous adhesion, and glial or glio-vascular proliferations observed in

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Fig. 6  Mechanical traction-induced macular edema. (a) Vitreomacular tractions leading to macular edema associated with an epiretinal membrane. (b) Epiretinal membrane and vitreomacular adhesion leading to cystoid macular edema and an irregular retinal surface

proliferative vitreoretinopathy following retinal detachment and proliferative d­ iabetic retinopathy must be individually analyzed to understand their role in ME formation.

Causes of Macular Edema ME can occur during the course of virtually every retinal disease at various phases of their evolution. The mechanisms of ME discussed above are intricate, but according to the causal disorder, certain mechanisms predominate.

Vasogenic Macular Edema Retinal Vein Occlusion Retinal vein occlusion leads to an increased intravascular pressure, blood-retinal barrier breakdown, and vascular leakage (Fig. 7a). Inner retinal hypoxia is associated with increased VEGF levels through HIF-1α, nitric oxide, and

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Fig. 7  Various causes of vasogenic macular edema imaged by color fundus photography and OCT. (a) Central retinal vein occlusion, characterized by flame-shaped hemorrhages, venous tortuosity, and few cotton-wool spots. Macular edema manifests by the intraretinal and subretinal accumulation of fluid. (b) Diabetic retinopathy and diabetic macular edema, displaying numerous dot-blot hemorrhages and lipid exudates. Optical coherence tomography shows diffuse cystoid macular edema and focal hyperreflective dots corresponding to the exudates. (c) Hypertensive retinopathy characterized by peripapillary distribution of cotton-wool spots, hemorrhages, and macular edema with subretinal fluid seen on optical coherence tomography

pro-­inflammatory cytokines that contribute to the inner blood-retinal barrier rupture [25]. Hypertension, frequently associated with retinal vein occlusion, aggravates ME by further increasing the intracapillary hydrostatic pressure in the Starling equation. In addition, secondary hypoxic alterations of RMG cells may also lead to cytotoxic edema [26]. In cases of retinal vein occlusion with associated ischemia, excitotoxicity due to glutamate excess induces intracellular neuronal edema secondary to cellular energy failure [27]. Subretinal fluid is present in about half of central retinal vein occlusions and indicates that outer retinal barrier breakdown contributes to ME formation [28]. Indeed VEGF release also acts on the RPE barrier function through the VEGF receptor 1 (Flt-1), whose expression is under HIF-1α regulation [29].

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Diabetic Macular Edema (DME) The pathogenesis of DME is complex and multifactorial. Before any microangiopathy is clinically observed, intraretinal local inflammation (i.e., neuroinflammation) causes neuronal damage [30, 31]. Specifically, activation of microglial cells contributes to the local release of nitric oxide, TNF-α, interleukins, and VEGF [32]. In physiologic conditions, microglia trafficking contributes to retinal homeostasis. Active clearance of microglial cells through RPE transcytosis was demonstrated in the rodent retina, which prevents subretinal accumulation of activated cells. With aging, this active clearance increases in order to compensate for enhanced microglial activation to age-related debris, while it decreases in case of diabetic retinopathy as a consequence of alteration of cytoskeleton plasticity [32, 33]. Accumulation of microglia in the diabetic retina was also demonstrated to occur in humans [34, 35]. Besides microglia, RPE and RMG cells submitted to chronic hyperglycemia, as well as metabolic and oxidative stress, also release inflammatory mediators such as VEGF through the activating transcription factor 4 (ATF4), IL-6, IL-8, TNF-α, MCP-1, chemokines, thrombospondin-1, and many other soluble factors [31, 36]. Microangiopathy results from several mechanisms: neurodegeneration [37], activation of the polyol pathway, nonenzymatic glycation of proteins, glucose auto-­ oxidation and oxidative stress, hyperglycemic pseudohypoxia, activation of protein kinase C by de novo synthesis of diacyl glycerol, and others [38, 39]. These hyperglycemia-­induced alterations of metabolic pathways affect endothelial cells and pericytes, leading to reduced pericyte coverage of retinal capillaries and microvascular degeneration [40–44]. Leukostasis, due to reduced deformability of leukocytes in diabetic patients; a reduced capillary lumen, due to basal membrane thickening and endothelial cell alterations; leukocyte activation by stromal cell-­ derived factor 1 (SDF-1); and increased adhesion all contribute to capillary occlusion [45]. Such vascular occlusion leads to increased levels of VEGF and other vascular permeability-inducing cytokines that contribute to vasogenic ME. Other vascular abnormalization processes such as the formation of microaneurysms contribute to focally enhanced fluid leakage and edema. The exact mechanisms leading to microaneurysms formation are not fully understood and involve VEGF, PGF [46], and pericyte alterations [47]. Activation of the renin-angiotensin system also contributes to the microvascular abnormalities in diabetic retinopathy, via the stimulation of growth factors such as VEGF, which induces vascular leakage, pericyte migration, angiogenesis, and fibrosis [48, 49]. The plasma kallikrein-kinin system (KKS) has also been related to diabetic ME. In advanced stages of diabetic retinopathy, the vitreous concentration of plasma kallikrein is increased. The intraocular activation of KKS induces retinal vascular permeability and ME, and it has been shown to be exacerbated in diabetic rats [50–52]. Compromised capillaries and leaky microaneurysms are the major vasogenic components in DME. But early alterations of the outer retinal barrier and the RMG drainage functions also contribute to DME [53–55].

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Fig. 8  Consequences of chronic hyperglycemia on the retina

Alteration of neuronal metabolism, glial cell death, and secondary ischemic cell suffering are also key players to DME through cytotoxic mechanisms. The role of insulin in DME remains disputed. Indeed, clinical trials and other studies have determined that initiation of acute intensive insulin therapy in patients with long-­ standing poor glycemic control results in a worsening of diabetic retinopathy [56]. A change in treatment from oral drugs to insulin in patients with non-insulin-­ dependent diabetes mellitus type 2 was associated with a significantly increased risk of retinopathy progression and visual impairment [57]. In summary, DME results from a combination of factors, whose contribution depends on the type of diabetes, the patient age, and their interaction with other systemic factors such as hypertension, vascular endothelial dysfunction, and lipid metabolism deregulation (Figs. 7b, 8, and 9). Hypertensive Retinopathy Acute arterial hypertension may provoke hypertensive retinopathy, hypertensive choroidopathy, and hypertensive optic neuropathy. Hypertensive retinopathy results from retinal capillary and precapillary occlusions, with a subsequent rupture of the inner blood-retinal barrier producing intraretinal edema. Hypertensive choroidopathy is characterized by focal areas of choriocapillaris occlusion resulting in RPE damage and rupture of the outer blood-retinal barrier leading to subretinal fluid accumulation and retinal edema (Fig. 7c) [58].

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Ganglion cell layer

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Cell death

Inner plexiform layer Müller cell swelling

Inner nuclear layer

Microvascular degeneration alteration blood barrier

Outer plexiform layer

Outer nuclear layer

Microglia activation migration

Receptor outer segments Retinal pigment epithelium Bruch’s mebrane

Inflammation

Alteration of outer retinal barriers

Choroid

Fig. 9  The events leading to diabetic macular edema

Inflammatory Macular Edema In the acute phases of an intraocular inflammatory process, ME is frequently not detected clinically. However, the rupture of the ocular barriers is obvious (as evidenced by the presence of aqueous or vitreous cells), supporting the idea that retinal barrier breakdown may not be sufficient to cause ME. On the other hand, ME is a frequent manifestation in chronic uveitis (Fig. 10b) and results from enhanced fluid entry through compromised inner and outer retinal blood barriers and from diminished fluid exit secondary to inflammatory alterations of RPE and RMG cells. Vasopermeability-inducing cytokines such as VEGF, IL-1β, IL-6, IL-8, TNF-α, and nitric oxide are produced at high levels by ocular resident cells, immune cells, and infiltrating cells and contribute to vasogenic ME [59, 60]. Similarly, the delayed accumulation of fluid in the macula observed in postoperative cystoid ME (Irvine-Gass syndrome, Fig. 10c) is related to blood-aqueous barrier breakdown mechanisms [61, 62].

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Fig. 10  Various causes of vasogenic macular edema seen on OCT. (a) Chronic central serous chorioretinopathy. (b) Extramacular toxoplasmic retinochoroiditis, with macular edema developing 4 months after onset of inflammation. Note the secondary epiretinal membrane that may aggravate the macular edema. (c) Irvine-Gass syndrome occurring 1 month after cataract surgery. (d) Active neovascular age-related macular degeneration with an advanced subretinal fibrotic complex

Macular Edema and Choroidal Neovascularization Choroidal neovascularization, either idiopathic or secondary to AMD (Fig. 10d), pathologic myopia, or inflammation, induces the accumulation of subretinal and intraretinal fluid as a result of the enhanced permeability of the neovascular component itself and the secondary blood-retinal barrier breakdown. VEGF is not significantly elevated in the ocular media of patients with wet AMD as compared to control, but the efficacy of anti-VEGF drugs in choroidal neovascularization-­ induced ME gives evidence that VEGF is a major pathogenic player [63–65].

Cytotoxic Macular Edema Pure cytotoxic ME is very rarely observed, and cytotoxic mechanisms are rather intricate and secondary to ME itself. Chemotherapy-Induced Macular Edema The best example of pure cytotoxic ME is caused by anti-microtubular agents, such us docetaxel and paclitaxel, used in the treatment of breast and ovarian cancers. Anti-microtubular agents have been reported to cause bilateral cystoid macular

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Fig. 11  An example of cytotoxic macular edema. Paracentral acute middle maculopathy with two ischemic lesions affecting mostly the inner nuclear and inner plexiform layers (star and arrow). The ischemic edema appears as focal whitish lesions on fundus examination (a), as hyporeflective lesions on near-infrared reflectance (b), and as focal hyperreflectivities on optical OCT (c, d)

edema without evidence of leakage in fluorescein angiography [66]. The targeting of cell microtubules alters molecular motors and subsequent membrane channel distribution, causing a dysfunction in drainage mechanisms and subsequent ME. Retinal/Choroidal Ischemia and Macular Edema Retinal arterial occlusions cause acute inner retinal edema secondary to intracellular swelling of neuronal and glial retinal cells, which manifests as an increased reflectivity on OCT, a well-known feature of central or branch retinal artery occlusions. In addition, localized retinal capillary ischemia also results in intracellular edema as recently described in paracentral acute middle maculopathy (Fig. 11) where no vascular angiographic leakage is present [67, 68]. Combined mechanisms may occur, as illustrated by the observation of paracentral acute middle maculopathy findings during the course of central retinal vein occlusions [69]. However, these alterations were not observed in areas of cystoid ME. In the majority of cystoid ME cases, the real contribution of pure cytotoxic ischemic mechanisms is difficult to evidence and has not been clearly demonstrated.

Conclusion Mechanisms leading to ME are usually intricate and difficult to discriminate in the various clinical presentations of ME. The recent multimodal combination of fluorescein, indocyanine green angiography, and spectral-domain optical coherence tomography (SD-OCT) helps to better understand the exact alterations of retinal

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structures that cause fluid accumulation within or under the retina. It also contributes to guide more appropriate and targeted treatments. However, most of the molecular mechanisms described in this chapter result from experimental models in rodents that do not have a macula. Since in humans edema forms mostly, if not exclusively, in the macula, the extrapolation of such mechanisms remains approximate and hazardous. Basic research and human pathology is still required to identify molecular targets specific to the macula that could be regulated by pharmacological agents.

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19. Wang M, Wong WT. Microglia-Müller cell interactions in the retina. Adv Exp Med Biol. 2014;801:333–8. 20. Reichenbach A, Wurm A, Pannicke T, et al. Müller cells as players in retinal degeneration and edema. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Für Klin Exp Ophthalmol. 2007;245:627–36. 21. Bringmann A, Kohen L, Wolf S, et al. Age-related decrease of potassium currents in glial (müller) cells of the human retina. Can J Ophthalmol J Can Ophthalmol. 2003;38:464–8. 22. Schubert HD. Cystoid macular edema: the apparent role of mechanical factors. Prog Clin Biol Res. 1989;312:277–91. 23. Simpson ARH, Petrarca R, Jackson TL. Vitreomacular adhesion and neovascular age-related macular degeneration. Surv Ophthalmol. 2012;57:498–509. 24. Steel DHW, Lotery AJ. Idiopathic vitreomacular traction and macular hole: a comprehensive review of pathophysiology, diagnosis, and treatment. Eye Lond Engl. 2013;27 Suppl 1:S1–21. 25. Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res. 2008;27:622–47. 26. Jaulim A, Ahmed B, Khanam T, Chatziralli IP. Branch retinal vein occlusion: epidemiology, pathogenesis, risk factors, clinical features, diagnosis, and complications. An update of the literature. Retina Phila Pa. 2013;33:901–10. 27. Chen J, Chiang C-W, Zhang H, Song S-K. Cell swelling contributes to thickening of low-dose N-methyl-D-aspartate-induced retinal edema. Invest Ophthalmol Vis Sci. 2012;53:2777–85. 28. Catier A, Tadayoni R, Paques M, et al. Characterization of macular edema from various etiologies by optical coherence tomography. Am J Ophthalmol. 2005;140:200–6. 29. Miyamoto N, de Kozak Y, Normand N, et al. PlGF-1 and VEGFR-1 pathway regulation of the external epithelial hemato-ocular barrier. A model for retinal edema. Ophthalmic Res. 2008;40:203–7. 30. Scholl S, Augustin A, Loewenstein A, et al. General pathophysiology of macular edema. Eur J Ophthalmol. 2011;21 Suppl 6:S10–9. 31. Abcouwer SF. Angiogenic factors and cytokines in diabetic retinopathy. J Clin Cell Immunol. 2013;11 (Suppl 1):1–12. 32. Karlstetter M, Scholz R, Rutar M, et al. Retinal microglia: just bystander or target for therapy? Prog Retin Eye Res. 2015;45C:30–57. 33. Grigsby JG, Cardona SM, Pouw CE, et al. The role of microglia in diabetic retinopathy. J Ophthalmol. 2014;2014:705783. 34. Omri S, Behar-Cohen F, de Kozak Y, et al. Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCζ in the Goto Kakizaki rat model. Am J Pathol. 2011;179:942–53. 35. Kaur C, Rathnasamy G, Ling E-A. Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina. J Neuroimmune Pharmacol Off J Soc Neuro Immune Pharmacol. 2013;8:66–78. 36. Wang L-L, Chen H, Huang K, Zheng L. Elevated histone acetylations in Müller cells contribute to inflammation: a novel inhibitory effect of minocycline. Glia. 2012;60:1896–905. 37. Simó R, Hernández C, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR). Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol Metab TEM. 2014;25:23–33. 38. Pfeiffer A, Schatz H. Diabetic microvascular complications and growth factors. Exp Clin Endocrinol Diabetes Off J Ger Soc Endocrinol Ger Diabetes Assoc. 1995;103:7–14. 39. Milne R, Brownstein S. Advanced glycation end products and diabetic retinopathy. Amino Acids. 2013;44:1397–407. 40. Lutty GA. Effects of diabetes on the eye. Invest Ophthalmol Vis Sci. 2013;54:ORSF81–7. 41. Ejaz S, Chekarova I, Ejaz A, et al. Importance of pericytes and mechanisms of pericyte loss during diabetes retinopathy. Diabetes Obes Metab. 2008;10:53–63. 42. Durham JT, Herman IM. Microvascular modifications in diabetic retinopathy. Curr Diab Rep. 2011;11:253–64.

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43. Bharadwaj AS, Appukuttan B, Wilmarth PA, et al. Role of the retinal vascular endothelial cell in ocular disease. Prog Retin Eye Res. 2013;32:102–80. 44. Arboleda-Velasquez JF, Valdez CN, Marko CK, D’Amore PA. From pathobiology to the targeting of pericytes for the treatment of diabetic retinopathy. Curr Diab Rep. 2015;15:573. 45. Chibber R, Ben-Mahmud BM, Chibber S, Kohner EM. Leukocytes in diabetic retinopathy. Curr Diabetes Rev. 2007;3:3–14. 46. Kowalczuk L, Touchard E, Omri S, et al. Placental growth factor contributes to micro-vascular abnormalization and blood-retinal barrier breakdown in diabetic retinopathy. PLoS One. 2011;6:e17462. 47. Beltramo E, Porta M. Pericyte loss in diabetic retinopathy: mechanisms and consequences. Curr Med Chem. 2013;20:3218–25. 48. Wilkinson-Berka JL. Diabetes and retinal vascular disorders: role of the renin-angiotensin system. Expert Rev Mol Med. 2004;6:1–18. 49. Clermont A, Bursell S-E, Feener EP. Role of the angiotensin II type 1 receptor in the pathogenesis of diabetic retinopathy: effects of blood pressure control and beyond. J Hypertens Suppl Off J Int Soc Hypertens. 2006;24:S73–80. 50. Feener EP. Plasma kallikrein and diabetic macular edema. Curr Diab Rep. 2010;10:270–5. 51. Liu J, Feener EP. Plasma kallikrein-kinin system and diabetic retinopathy. Biol Chem. 2013;394:319–28. 52. Wilkinson-Berka JL, Fletcher EL. Angiotensin and bradykinin: targets for the treatment of vascular and neuro-glial pathology in diabetic retinopathy. Curr Pharm Des. 2004;10:3313–30. 53. Iandiev I, Pannicke T, Reichenbach A, et al. Diabetes alters the localization of glial aquaporins in rat retina. Neurosci Lett. 2007;421:132–6. 54. Omri S, Behar-Cohen F, Rothschild P-R, et al. PKCζ mediates breakdown of outer blood-­ retinal barriers in diabetic retinopathy. PLoS One. 2013;8:e81600. 55. Krügel K, Wurm A, Pannicke T, et al. Involvement of oxidative stress and mitochondrial dysfunction in the osmotic swelling of retinal glial cells from diabetic rats. Exp Eye Res. 2011;92:87–93. 56. Anon. Diabetic retinopathy after two years of intensified insulin treatment. Follow-up of the Kroc Collaborative Study. The Kroc Collaborative Study Group. JAMA. 1988;260:37–41. 57. Henricsson M, Janzon L, Groop L. Progression of retinopathy after change of treatment from oral antihyperglycemic agents to insulin in patients with NIDDM. Diabetes Care. 1995;18:1571–6. 58. Verougstraete C. Macular edema in arterial hypertension. Bull Société Belge Ophtalmol. 1991;240:23–33. 59. Klaassen I, Van Noorden CJF, Schlingemann RO. Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions. Prog Retin Eye Res. 2013;34:19–48. 60. Bonfioli AA, Damico FM, Curi ALL, Orefice F. Intermediate uveitis. Semin Ophthalmol. 2005;20:147–54. 61. Ersoy L, Caramoy A, Ristau T, et al. Aqueous flare is increased in patients with clinically significant cystoid macular oedema after cataract surgery. Br J Ophthalmol. 2013;97:862–5. 62. Pande MV, Spalton DJ, Kerr-Muir MG, Marshall J. Postoperative inflammatory response to phacoemulsification and extracapsular cataract surgery: aqueous flare and cells. J Cataract Refract Surg. 1996;22 Suppl 1:770–4. 63. Solomon SD, Lindsley K, Vedula SS, et al. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014;(8): CD005139. 64. Vedula SS, Krzystolik MG. Antiangiogenic therapy with anti-vascular endothelial growth factor modalities for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2008;(2):CD005139. 65. Wang E, Chen Y. Intravitreal anti-vascular endothelial growth factor for choroidal neovascularization secondary to pathologic myopia: systematic review and meta-analysis. Retina Phila Pa. 2013;33:1375–92.

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66. Liu CY, Francis JH, Brodie SE, et al. Retinal toxicities of cancer therapy drugs: biologics, small molecule inhibitors, and chemotherapies. Retina Phila Pa. 2014;34:1261–80. 67. Yu S, Pang CE, Gong Y, et al. The spectrum of superficial and deep capillary ischemia in retinal artery occlusion. Am J Ophthalmol. 2015;159:53–63. e1–2. 68. Sarraf D, Rahimy E, Fawzi AA, et al. Paracentral acute middle maculopathy: a new variant of acute macular neuroretinopathy associated with retinal capillary ischemia. JAMA Ophthalmol. 2013;131:1275–87. 69. Rahimy E, Sarraf D, Dollin ML, et al. Paracentral acute middle maculopathy in nonischemic central retinal vein occlusion. Am J Ophthalmol. 2014;158:372–380.e1.

Chapter 3

Diagnosis of Cystoid Macular Edema: Imaging Dilraj S. Grewal and Glenn J. Jaffe

Introduction Early detection of cystoid macula edema (CME) is critical for diagnosis and management. Traditional methods of accessing macular edema include contact and noncontact slit lamp biomicroscopy, indirect ophthalmoscopy, fluorescein angiography (FA), and fundus stereo photography. However the interpretation of their results can be subjective, and subtle changes in retinal thickness in early CME may not be evident. Optical coherence tomography (OCT) correlates well with retinal histology [1] and can be used to quantitatively and qualitatively monitor retinal thickness over time. Compared to biomicroscopy and FA, OCT is more sensitive in detection of macular edema and subretinal fluid, and subclinical macular edema is often only detected by OCT. In general, CME is visualized on OCT scans as multiple circular cystic spaces in the retina, indicating intraretinal edema. The cystic spaces are round or oval and originate around the outer plexiform layer (OPL) but can progress to involve the photoreceptor layer and the inner retinal layers. Occasionally, cystic retinal edema can enlarge and have the appearance of a foveal pseudocyst. OCT is highly effective to visualize CME because the cystoid fluid has less optical scattering than the surrounding retinal tissues. Advancements in imaging technologies and resolution have improved our understanding of CME due to different pathologies and their differentiating characteristics. In this chapter, we discuss the imaging methods to diagnose CME of different etiologies.

D.S. Grewal, MD • G.J. Jaffe, MD ( ) Duke Eye Center, Box 3802, Durham, NC 27705, USA e-mail: [email protected] © Springer International Publishing Switzerland 2017 S. Schaal, H.J. Kaplan (eds.), Cystoid Macular Edema, DOI 10.1007/978-3-319-39766-5_3

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CME Associated with Diabetes: Diabetic Macular Edema Diabetic macular edema (DME) results from pathologic leakage from damaged retinal microvasculature and insufficient clearance of plasma by Müller and retinal pigment epithelial (RPE) cells. Vascular leakage and intraretinal fluid (IRF) accumulation can be imaged clinically using FA in eyes with DME. The classification of DME has evolved considerably since the Early Treatment Diabetic Retinopathy Study (ETDRS) characterization as focal or diffuse based on clinical examination and FA findings [2, 3]. OCT permits analysis of outer retinal layer integrity in DME, which is linked to the visual prognosis [4–10]. For example, disruption of the hyperreflective ellipsoid layer indicates macular photoreceptor damage and is associated with decreased visual acuity. Intraretinal fluid, increased retinal thickness, macular ischemia, and foveal exudates also contribute to the poor prognosis in DME [11]. Based on a 10 % test-retest variability of OCT retinal thickness measurements in diabetics, >10 % thickness change is often considered clinically relevant in DME [12]. Different patterns of fluid accumulation have now been described. Otani described three patterns of structural changes in DME: diffuse retinal thickening (DRT), CME, and serous retinal detachment (SRD) [13]. They reported that DRT (focal or diffuse edema) first appeared as a reduction in the tissue reflectivity and increased retinal thickness, followed by a “spongy” appearance of the retina. CME was defined as the accumulation of IRF in well-defined spaces. SRD was usually due to chronic edema and was characterized by coalescence of cystic cavities and sensory retinal elevation. Kim et al. similarly described five different morphologic patterns on OCT [14]: DRT, CME, SRD, posterior hyaloid traction (PHT) without macular tractional retinal detachment (TRD), and PHT with TRD. DRT was defined as increased retinal thickness with areas of reduced intraretinal reflectivity (Fig. 1). CME was characterized by intraretinal cystoid-like cavities defined as large ovoid hyporeflective areas

Fig. 1 Diffuse retinal thickening pattern of diabetic macular edema (DME) with increased retinal thickness and a “spongy” appearance of the retina. There is a reduction in the reflectivity of the outer retinal layers due to the overlying cystic spaces and intraretinal fluid (top). Fluorescein angiography (bottom) demonstrates generalized leakage prominent on late frames without a discretely identifiable source

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Fig. 2 Cystoid macular edema (CME) pattern of DME: Retinal thickening and hyporeflective cystic spaces in the inner retina separated by hyporeflective septae with subfoveal subretinal fluid (right). Fluorescein angiogram (left) shows paravoeal petaloid leakage corresponding to the CME and leakage temporally due to microaneurysms

Fig. 3 DME with posterior hyaloid traction (PHT) without tractional retinal detachment. Top figure shows diffuse DME with large intraretinal cystic spaces and intraretinal fluid and an adherent posterior hyaloid. Following anti-vascular endothelial growth factor (VEGF) therapy, there is an improvement in intraretinal and subretinal fluid but a persistent foveal intraretinal cyst and posterior hyaloidal traction on the fovea (bottom figure)

separated by hyperreflective septae (Fig. 2). PHT was defined as a highly reflective band over the retinal surface and SRD appeared as a dark accumulation of subretinal fluid beneath the highly reflective and dome-like elevation of detached retina. They used the highly reflective band representing the outer surface of the detached retina to differentiate SRF from IRF (Fig. 3). TRD was identified as the area of low signal underlying the highly reflective border of the detached retina, often in a peaked configuration (Fig. 4). These TRDs may often be subclinical and visualized only on OCT [15]. In addition to these descriptive classifications, various intraretinal microstructural anatomical characteristics have been described in eyes with DME. These include hyperreflective foci (HRF), a morphologic sign of accumulation of IRF and lipid extravasation, suggested to be precursors of hard exudates before they become clinically visible [11, 16, 17]. Outer retinal HRF have been associated with disrupted ELM or ellipsoid layer and decreased VA, suggesting photoreceptor degeneration in DME. Pemp et al. [18] showed that DME reduction during anti-VEGF

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Fig. 4 DME with a tractional retinal detachment: Intraretinal cystic spaces superior and inferior to fovea with a tractional retinal detachment in the superior and inferior macula in a peaked configuration visualized on vertical OCT scan. Hyperreflective opacities in the vitreous represent a mild vitreous hemorrhage

therapy was accompanied by dynamic rearrangement of these intraretinal exudates. Type 1 diabetes patients have fewer HRF than with type 2 diabetes [19]. Gelman et al. [20] reported hyperreflective dots in a contiguous ring around the inner wall of cystoid spaces in the OPL, a pattern that they referred to as the “pearl necklace sign.” This configuration was found adjacent to hard exudates in the OPL, and the hyperreflective material was speculated to be composed of lipoproteins or lipidladen macrophages. Microaneurysms (MAs) in DME have also been evaluated on OCT. The OCT parameters of leaking microaneurysms include outer and inner diameter of the microaneurysm and wall thickness [21, 22]. Hyperreflective spots on OCT in microaneurysm lumens have been suggested to be cellular components such as erythrocytes, leukocytes, and lipid deposits [22]. Lee et al. characterized microaneurysm closure following focal laser photocoagulation in DME using simultaneous FA and OCT [23]. Microaneurysm closure following focal laser photocoagulation was characterized either by hyperreflective spots or complete disappearance without any hyporeflectivity. Smaller microaneurysms with a heterogeneous lumen were more likely to close [23]. It is of critical importance to identify anatomical biomarkers of DME that predict visual outcome and guide the choice of candidate drugs for interventional trials. However, a reliable anatomical biomarker of VA in patients with DME has yet to be firmly established. OCT retinal thickness measurements, although an important clinical and anatomic evaluation tool, are not an ideal surrogate for VA as a primary outcome in DME studies. Although OCT-derived central retinal thickness is commonly utilized in DME evaluation and management, central foveal thickness (CFT) explains no more than 27 % of the variation in VA [24]. There have been attempts to identify various OCT-based biomarkers that better correlate anatomic microstructure with function and predict visual recovery in eyes with DME. These microstructures include the external limiting membrane (ELM), integrity of the ellipsoid layer (formerly described as the inner segment/outer segment photoreceptor junction) [6, 8, 25], thickness of the photoreceptor outer segments, status of the cone outer segment tips (COST) [7], presence of hyperreflective foci [11, 17, 26], and subretinal fluid (SRF) [27].

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Horri et al. [28] showed that after triamcinolone acetonide treatment for DME, reduced reflectivity in foveal cystoid spaces was associated with a rebound in macular thickening and visual deterioration. Cystic macular changes have been associated with photoreceptor layer damage to a greater extent than diffuse edema and serous retinal detachment. ELM breakdown has been shown to lead to subfoveal SRF [16]. Foveal photoreceptor layer status has been closely related to visual acuity in patients with DME [9, 29]. However, the influence of the foveal avascular zone size on the photoreceptor layer integrity is yet to be clearly defined. Some of the changes evaluated on OCT persist even following DME treatment. Despite treatment and resolution of DME and restoration of macular thickness, the ganglion cell inner plexiform layer thickness in eyes with resolved DME is thinner than that in eyes without DME. This difference correlates with decreased visual acuity, suggesting that inner retinal alterations in DME may lead to visual deficiency that persists after treatment [30]. Lee et al. demonstrated that ischemia in eyes with DME caused photoreceptor outer segment shortening and ellipsoid layer disruption, resulting in outer retinal layer atrophic changes and subsequent visual loss [31]. Soliman et al. [32] found that cystoid spaces, especially in the INL, were associated with worse VA outcome after macular grid laser photocoagulation for DME. Areas beneath the OPL cystoid spaces have been shown to have longer spans of disrupted ellipsoid layer and ELM [29]. There is general consensus that a correlation exists between retinal thickness and visual acuity (VA) in patients with DME [14]. The OCT pattern that was found to be associated with worse VA was “CME”; eyes with CME had a 0.40 reduction in logMAR acuity compared with eyes that had DME without this pattern [14]. Retinal inner layer disorganization within the central 1 millimeter (mm) foveal area predict worse VA in eyes with center-involved DME [33, 34]. This anatomic feature had a higher correlation with VA than central retinal thickness, large intraretinal cysts, or current glycemic status. Disorganization of the retinal inner layers could identify eyes with a high likelihood of subsequent VA improvement or decline; disorganization of the retinal inner layers affecting 50 % or more of the central 1-mm-wide zone centered on the fovea had worse VA [33]. It has been proposed that this anatomic change represents disorganization or destruction of cells within the inner retinal layers, including bipolar, amacrine, or horizontal cells, and possibly indicates a disruption of pathways that transmit visual information from the photoreceptors to the ganglion cells. Histologic assessment of these changes would help confirm this hypothesis. If true, early-stage retinal inner layer disorganization could be used as a prognostic visual acuity marker in untreated eyes with DME. Over recent years, in addition to improved resolution, the application of image processing to OCT image interpretation has mostly focused on the development of automated retinal layer segmentation methods [35, 36]. There have been several challenges in this effort. OCT images are often corrupted by speckle noise and need to undergo noise reduction to reduce its effect on the classification results. Speckle occurs in OCT due to the random interference of waves reflected from subresolution variances within the object. Maintaining edge-like features in the image after speckle denoising is particularly important for segmentation. It is easier to segment the retinal layers in early stages before the appearance of severe pathology [35, 37].

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CME comprises a contiguous fluid-filled space containing columns of tissue; these spaces may falsely appear as separated cysts when viewed by OCT. It has been therefore suggested that retinal volume may be a better predictor of VA than central macular thickness in CME [38]. Automated segmentation of the cystoid fluid volume in CME has been described to identify regions of cystoid fluid within a threedimensional retinal stack of images. However the correlation of this total cystoid volume with VA and its ability to distinguish intraretinal cysts from other features such as SRF or an epiretinal membrane (ERM) has yet to be established. Automated layer segmentation software allows detection of relatively few anatomical boundaries, which may limit its application in “real-world” clinical OCT images which are often not of the same quality as experimental images attained through study imaging sessions.

Imaging the Choroid in DME There has been recent interest in the role of choroidal imaging in DME. The choroidal vasculature, especially the choriocapillaris layer, is critical to maintain the neurosensory retina as it nourishes the outer retina. Definitive changes in the choroid have been confirmed on histopathology [39]. New imaging techniques including long-wavelength OCT, polarization-sensitive OCT, and standard spectral-domain (SD) OCT with an enhanced depth-imaging mode allow assessment of choroidal thickness. The choroid of patients with diabetic retinopathy and DME is thinner than that of age-matched healthy people as well as fellow eyes without DME [40, 41]. Subfoveal medium choroidal vessel layer and choriocapillaris layer thicknesses have also shown to be reduced in DME [42]. In contrast, Kim et al. showed that the subfoveal choroid was thicker in eyes with DME than in those without and was thickest in eyes with SRD-type DME [43]. Central choroidal thickness decreases 6 months after anti-vascular endothelial growth factor (VEGF) therapy for DME [44]. Eyes with thicker baseline subfoveal choroidal thickness may have better short-term anatomic and functional responses [45].

Fluorescein Angiography in DME While OCT provides valuable morphologic information and is useful to monitor DME and its response to treatment [46], FA offers critical biological information such as location, intensity, and leakage source. Furthermore leakage area as measured by FA continues to be a relevant secondary endpoint in major studies of DME treatment [47]. Although FA provides additional information about DME that is complementary to OCT, change in FA leakage over time is considered by many to be a more valu-

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able metric than the absolute leakage at a single timepoint. This is partly because quantification of features on FA is typically not as reproducible compared to other imaging modalities such as OCT. Identification of DME subtypes by FA has potential to guide therapy and monitor disease activity. Various subtypes of DME have been proposed based on differences in the pattern of fluorescein leakage [48]. Focal leakage manifests as discrete foci of leakage on early FA frames and corresponds to MAs. The diffuse subtype is characterized by generalized leakage prominent on late FA frames without a discretely identifiable source (Fig. 1). The angiographic appearance in eyes with DME can include either of these two leakage patterns, or a mixture of both [49]. Correlation between the FA macular leakage pattern and the edema morphology on OCT has been shown [21, 32, 50–52]. Variability of OCT reflectivity levels in the foveal cystoid spaces that corresponds to fluorescein pooling has been shown in DME. However the clinical relevance of this finding remains to be established [53]. While reproducible quantitative and qualitative analysis of FA is possible by experienced graders in the setting of a formal image reading center, its use for subtyping in the clinical setting is hindered by the subjective nature of FA interpretation. There has been long-standing interest in objective methods to quantify FA leakage. Segmentation of leakage on fluorescein angiograms obtained in the clinic is challenging, partly due to difficulties with FA sequence registration. There have been attempts to automate MA detection [54, 55], extraction of vessels [56], foveal avascular zone (FAZ) detection [57], and even automated leakage detection or quantification [58–61]. Rabbani et al. recently described a fully automated image segmentation algorithm without manual inputs to reproducibly and accurately quantify DME leakage area [62]. Using OCT and FA, Bolz et al. [21, 63] proposed the SAVE protocol for DME categorization. “S” stands for subretinal fluid, “A” for area, “V” for vitreoretinal interface abnormalities, and “E” for etiology. Based on etiology, DME leakage was categorized as focal or multifocal (FA with definable leakage source), non-focal capillary leakage (FA without definable leakage source), macular or peripheral ischemia (ischemia anywhere on FA associated with focal or non-focal edema on OCT), and atrophic edema (cystoid swelling on OCT). Newer technologies like en face OCT, OCT angiography, and retromode scanning laser ophthalmoscope (SLO) are also being investigated in DME.

Pseudophakic Cystoid Macular Edema CME associated with cataract extraction was initially described by A. Ray and Irvine, Jr., in patients with unexplained visual loss following intracapsular cataract extraction. Subsequently, this phenomenon was identified by Gass and Norton as macular edema with a classic perifoveal petaloid FA staining pattern and late nerve leakage [64, 65].

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Fig. 5 Pseudophakic CME with cystic spaces and subfoveal subretinal fluid (bottom). There is parafoveal petaloid leakage on the fluorescein angiogram and mild leakage at the optic nerve (top)

More recently, OCT characteristics of pseudophakic CME have been described. These features include macular thickening and cystic spaces in the OPL, occasionally with subfoveal fluid (Fig. 5). An OCT-based automated statistical classification approach to differentiate DME from pseudophakic CME has been evaluated. Grading parameters included assessment of CME pattern, cyst distribution in ETDRS grid, morphologic features, and quantitative parameters such as individual layer thickness. Munk et al. [66] showed that higher central retinal thickness/volume ratio, the absence of ERM, and solely inner nuclear layer (INL) cysts indicated pseudophakic CME; a higher ONL/INL ratio, the absence of SRF, the presence of hard exudates, microaneurysms, and ganglion cell layer and/or retinal nerve fiber layer cysts favored DME. The optical density of subretinal fluid in DME and pseudophakic CME was similar [67]. Oh and associates reported the presence of vitreous hyperreflective dots following phacoemulsification. The number of hyperreflective dots detected 1 week following surgery predicted the development of CME at 1 month [68]. These vitreous hyperreflective dots were thought to correspond to lens fragments, denatured proteins, or clumps of intraocular cells. They were >20 μm in size which was larger than vitreous cavity cells seen as ~15 μm hyperreflective dots on OCT in uveitic eyes [69]. The authors concluded that despite the unclear nature of these dots, their association with pseudophakic CME suggested a relation to postoperative inflammation and vascular permeability. Evaluation for previously undiagnosed photoreceptor disruption is important in assessment of eyes with unexplained vision loss despite resolution of pseudophakic CME. Using a 4 μm resolution OCT [70], persistent anatomic alteration of photoreceptors, described as a blurring of cone photoreceptor outer segment tips, correlated with reduced visual acuity in eyes with resolved pseudophakic CME that did not achieve 20/20 visual acuity compared with eyes that did.

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Other OCT characteristics associated with pseudophakic CME include vitreomacular traction (VMT), extrafoveal vitreoretinal traction [71, 72], ERM, or ERM following prior ERM peeling [73, 74]. Odrobina et al. [75] recently suggested that a thinner choroid in eyes with pseudophakic CME compared to fellow eyes indicate that reduced choriocapillaris blood flow may be a possible CME etiologic factor. Others have reported, however, that eyes with pseudophakic CME had greater thickening of the subfoveal choroid, which preceded CME development by 1 month [76].

CME Associated with Retinal Vascular Occlusions CME, a major cause of visual acuity loss in patients with retinal vascular occlusion (RVO) [77], is characterized by intraretinal fluid accumulation with diffuse retinal thickening or formation of cystoid spaces, SRF accumulation, or macular traction due to ERM formation (Figs. 6 and 7). OCT assessment of retinal thickness and structural changes provides useful information to determine treatment strategy for RVOassociated CME and to predict the long-term visual prognosis. OCT anatomic parameters such as foveal thickness, serous retinal detachment, central cystoid spaces, and pigment epithelial changes correlate with decreased visual recovery after RVO [78, 79]. Various RVO anatomic biomarkers have been evaluated with OCT. In eyes with central retinal vein occlusion (CRVO), foveal thickness >700 μm should raise suspicion for an ischemic form of CRVO [80]. In BRVO, cystoid spaces >600 μm in diameter have been associated with a longer occlusion of duration and poor visual

Fig. 6 CME in nonischemic central retinal vein occlusion (CRVO) with diffuse retinal thickening, cystoid spaces, and accumulation of subretinal fluid (top). Fluorescein angiogram shows diffuse parafoveal leakage (bottom)

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Fig. 7 CME in branch retinal vein occlusion (BRVO) with intraretinal cystoid spaces, no subretinal fluid (top), petaloid leakage on fluorescein angiogram (middle), and parafoveal hyper fundus autofluorescence (FAF) pattern on fundus autofluorescence (bottom)

improvement with bevacizumab therapy [81, 82]. Loss of the subfoveal ellipsoid layer and the absence of the inner retinal layers on OCT are correlated with poor visual outcomes in patients with CRVO [83] and branch retinal vein occlusion (BRVO) [79, 84, 85]. In addition, loss of the inner retinal layers correlates with macular ischemia diagnosed in early FA frames [78]. Tsujikawa and associates reported that a breakdown of the ELM barrier function caused movement of IRF into the subretinal space in RVO-associated CME [86]. They also reported highly reflective vertical lines beneath the cystoid spaces that were proposed to represent tracks through which the IRF within the cystoid spaces flowed into the subretinal space [16, 86, 87]. Hasegawa et al. also observed highly

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Fig. 8 CME in BRVO with subretinal fluid (top) and a hyperreflective track line (below, white arrow) at the fovea after resolution of CME

reflective vertical lines termed “track lines” beneath the cystoid spaces in the OCT images similar to those described by Tsujikawa et al., but note that the lines persisted despite resolution of CME [86, 88]. It has been suggested that the track lines probably developed when the CME resolved rapidly by the treatment. They observed these track lines at the fovea after resolution of CME associated with BRVO (Fig. 8). Track lines are thought to cause the localized damage of the photoreceptors. Hyperreflective foci are track line components, and it is thought that hyperreflective foci deposited in the outer retina causes the photoreceptor damage [11, 16, 89–91]. The specific mechanism that accounts for photoreceptor damage is unknown, but it has been proposed that macromolecules in IRF pass through small ELM disruptions and cause photoreceptor damage. Therefore, the track lines may be associated with localized rather than diffuse photoreceptor damage. Hasegawa et al. [88] suggested that the track lines are associated strongly with an initially disrupted ELM and thus might not be detected in eyes with spontaneous CME resolution. Track lines may thus be a useful marker of photoreceptor damage in eyes with resolved macular edema associated with BRVO. Another biomarker that has been evaluated is an inward curvature of the foveal ellipsoid zone, seen in normal eyes, and termed the “foveal bulge” [92]. The foveal bulge is a good marker of visual functional in eyes with resolved BRVO-associated CME. The presence of the foveal bulge indicates better BCVA after resolution of the macular edema associated with BRVO [92]. In eyes with an intact foveal ellipsoid layer after resolution of BRVO-associated CME, the retinal thickness at the foveal center was thinner, and the photoreceptor OS length was shorter in the group without a foveal bulge than in the group with it [92]. The study suggested that CME damages foveal photoreceptor outer segments resulting in the absence of a foveal bulge. Ellipsoid layer disruption at the central fovea has been shown in eyes with poor visual acuity despite complete resolution of CME (Fig. 9) [79, 83, 85]. It has also been shown that the integrity of the ellipsoid layer correlates with VA in eyes with resolved RVO-associated CME [92–94]. An association between the initial foveal thickness and final VA is somewhat controversial. While some have reported a correlation between the initial foveal thickness and final VA in eyes with RVO and persistent CME after treatment [82, 85], others have not observed this association [82, 94].

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Fig. 9 Lack of visual acuity improvement in an eye (stable at 20/60) with CME associated with non-ischemic CRVO (top) despite near-complete resolution of CME following treatment with anti-vascular growth factor injections attributed to ellipsoid layer disruption at the central fovea (bottom)

Fig. 10 Hyperreflective foci in an eye with BRVO and CME (top) with increased subretinal lipid exudates 8 weeks later (bottom). It has been suggested that these foci could be small intraretinal protein and/or lipid deposits and precursors of hard exudates

Various anatomical characteristics have been evaluated as potential prognostic indicators in RVO-associated CME. In CRVO-associated CME, the presence of SRF or the diameter of cystoid spaces has not been shown to be predictive for treatment outcome [82]. Ellipsoid layer integrity and ELM status at baseline correlate with better visual outcomes after anti-VEGF treatment for RVO- associated CME [94, 95]. Severe photoreceptor damage during the acute or chronic phase of RVO might lead to a substantial photoreceptor outer segment defect, resulting ellipsoid zone loss [79, 83]. Kang et al. suggested that hyperreflective foci detected on the baseline OCT were predictive of visual outcomes following anti-VEGF treatment [94]. Fine hyperreflective foci found on OCT, however, could not be found on fundus photographs taken simultaneously. In contrast, confluent hyperreflective foci on OCT were detected as hard exudates in the corresponding fundus photograph, and a previous study suggested that these fine foci, characterized by the same

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Fig. 11 CME associated with a superotemporal BRVO with intraretinal hemorrhages: fundus autofluorescence (FAF) demonstrates hyperautofluorescence in the fovea corresponding to the CME and hypoautofluorescence superiorly corresponding to the hemorrhages (top), vertical OCT scan shows a superior macular edema pattern (bottom)

hyperreflectivity as confluent dots, might be small intraretinal protein and/or lipid deposits which are precursors of hard exudates (Fig. 10) [16]. In eyes with BRVO, ELM and ellipsoid layer were significantly more disrupted in eyes that had hyperreflective foci as part of the track lines in the outer retinal layers [88]. These findings suggested that photoreceptor status, rather than foveal thickness, was more likely correlated with the final BCVA, after CME treatment in BRVO. Asymmetric CME distribution in the vertical scan is often pathognomonic for BRVO. Because of the higher prevalence of superotemporal vein occlusions [96], vertical line scans show a superior macular edema pattern in BRVO with a higher prevalence of cysts in the inner superior ETDRS subfield (Fig. 11). Choroidal thickness has also been evaluated in RVO-associated CME. In both BRVO and CRVO, the choroidal thickness is greater than in the unaffected fellow eyes, and the choroidal volume is decreased following anti-VEGF treatment [97, 98].

CME Associated with Vitreoretinal Interface Abnormalities An ERM results from proliferative change at the vitreoretinal interface. Tangential traction from ERM may cause macular thickening with or without fluorescein leakage. ERMs can also distort the underlying retina and create cystoid spaces. On OCT the posterior hyaloid, a minimally reflective structure, can often be differentiated from an ERM, which is highly reflective [99]. Wilkins et al. described two patterns of ERM adherence [100]: a broadly attached ERM, which was most common (Fig. 12), and less frequently, ERM with focal attachments. OCT has also

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Fig. 12 CME with intraretinal cystoid spaces and subretinal fluid associated with a broad epiretinal membrane. The epiretinal membrane has caused distortion of the inner retina

Fig. 13 Vitreomacular traction resulting in increased foveal thickness, intraretinal cysts and disruption of the ellipsoid layer (top), and restoration of normal foveal contour along with resolution of cystic spaces following spontaneous release of traction (bottom)

been helpful to confirm the relationship between a posterior vitreous detachment and ERM and is valuable to follow ERM natural history. Partial or complete PVD has been found in 80–95 % of eyes with idiopathic ERM [101–103]. VMT is an anomalous, posterior vitreous attachment that causes macular anteroposterior traction in areas of residual vitreous adhesion. The adherent vitreous cortex results in a broad, often dumbbell-shaped region, encompassing the macula and optic nerve [104]. This traction is associated with cystoid macular thickening (Fig. 13). The phase III trials of Microplasmin Intravitreal Injection for Non-surgical Treatment of Focal Vitreomacular Adhesion (MIVI-TRUST) evaluated enzymatic vitreolysis with ocriplasmin. In these trials, OCT and clinical examination was used to assess retinal morphology; these investigations confirmed the superiority of OCT to clinical examination [105]. The study described two subclasses of VMT: focal (≤1500 μ) and broad (>1500 μ) adhesion [106–108]. Koizumi et al. [107] showed that eyes with focal VMT had a foveal cavitation, whereas eyes with broad VMT had more widespread CME. In VMT, the posterior hyaloid usually appears hyperreflective and thickened on OCT. Yamada and Kishi [109] described two types of partial PVD patterns – incomplete vitreous detachment nasally and temporally causing a V-shaped pattern with attachment only at the fovea and the second type showing persistent nasal attachment and detachment temporal to the fovea. The first type of PVD had postoperatively better visual outcomes compared with the second type.

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CME Associated with Uveitis Hassenstein and colleagues were the first to describe the use of OCT in uveitis. This group found that OCT was useful in detection of early CME and monitoring of treatment efficacy, especially when vitreous cells were present [110, 111]. Specific OCT patterns have been identified in CME associated with uveitis, similar to those reported in DME: diffuse macular edema (characterized by increased retinal thickness, disturbance of the layered retinal structure or sponge-like low reflective areas) (Fig. 14), cystoid macular edema (characterized by clearly defined intraretinal cystoid spaces) (Fig. 15), and serous retinal detachment (characterized by a clean separation of the neurosensory retina from the RPE/choriocapillaris band) (Fig. 16) [13, 111, 112]. Iannetti et al. imaged 43 eyes and found that 58 % had cystoid macular edema, 42 % had diffuse macular edema, and 28 % of all cases had serous retinal detachment. The relative frequency of the three different patterns in uveitis varies depending on the patient selection criteria [111, 113, 114].

Fig. 14 Diffuse pattern of uveitic CME associated with sarcoid. The retina has inner and outer plexiform layer cystoid spaces, hyperreflective foci, and subretinal fluid

Fig. 15 CME associated with autoimmune retinopathy with parafoveal hyperautofluorescence on FAF (top). There is retinal thickening in the fovea with intraretinal cystoid spaces and diffuse retinal thinning with outer retinal loss in the surrounding temporal area without edema (bottom) and a corresponding hypo autofluorescent pattern on FAF

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Fig. 16 Increased fundus hyperautofluorescence on FAF upon development of intraretinal cystoid spaces and subretinal fluid (bottom) in CME associated with birdshot chorioretinopathy

OCT also detects ERM, often with concurrent vitreoretinal traction in a higher percentage of uveitic CME eyes compared to ophthalmoscopy [112]. A tractional mechanism has also been hypothesized as a cause of or contributor to uveitic CME. The presence of an ERM is independent from the site of inflammation, type of edema, and macular thickness [112]. A ringlike non-cystic thickening that surrounds the foveal center has been seen in eyes with iridocyclitis. It has been theorized that the same pathophysiological mechanism that underlies this non-cystic ringlike thickening accounts for the CME in eyes with anterior uveitis. This thickening, lasting 260 μm) was optimal to predict more than a 10-letter change in VA, with 77 % sensitivity and 75 % specificity. This threshold is important for uveitis trials wherein uveitic CME improvement is monitored through changes in central subfield thickness and associated with clinically meaningful VA changes. The MUST trial also showed that OCT and FA only agreed moderately to identify uveitic CME in eyes with intermediate, posterior, and panuveitis, probably because macular thickening on OCT (time domain) and macular leakage are related but nonidentical pathologic characteristics [130]. Fluorescein leakage indicates pathological leakage from blood vessels, which is often but not always associated with macular thickening. Reasons for lack of thickening when there is fluorescein vascular leakage include the following non-mutually exclusive mechanisms: severely damaged atrophic maculae, with superimposed ongoing inflammatory leakage, a macula with very recent leakage that has preceded retinal thickening, macular distortion secondary to ERM without associated thickening, or a steady state whereby macular leakage is balanced by physiologic fluid egress from the macular retina [130]. The MUST trial also showed that the presence of macular cysts on OCT was associated with increased retinal thickness by OCT, hyperfluorescent cystoid spaces on FA, and macular leakage on FA [130]. Small cysts and ERMs involving the center were common in intermediate and posterior/panuveitis and required systemic corticosteroid therapy [131]. The MUST reading center methodology defined ERM as a hyperreflective layer with a bridging effect over the inner retinal layers, thus potentially excluding broadly adherent ERMs if their reflectivity merged with the nerve fiber layer. Corrugation of inner retinal layers was also considered insufficient to identify an ERM [131]. These results suggest that in uveitic CME, FA and OCT offer related yet unique clinically important information on macular pathologic features.

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Similar to DME, the relationship between VA and CME in uveitis is imperfect. Payne et al. [132] determined the utility of logarithmic transformation of OCT retinal thickness data to assess clinically meaningful changes in uveitic CME. Log scale OCT thickness correlated with logMAR visual acuity suggesting its use as an objective measure in uveitic CME [132]. These researchers also showed that in uveitic CME, the volume between the plexiform layers was the best indicator of visual function at baseline [38]. Brar et al. reviewed FA and OCT images of 87 patients with CME due to diabetes, ERM, uveitis, pseudophakia and vein occlusion. They concluded that while cystoid leakage on FA was always associated with cystic OCT changes, diffuse non-cystoid leakage on FA was associated with thickening and distortion of the retinal layers without cyst formation [133]. Diffuse uveitic CME has been associated with a poor visual prognosis and a poor prognosis for vision recovery [124]. SRF, however, is associated with a high probability of vision recovery in uveitic CME [134]. This is in contrast to SRF in DME that is associated with a poor prognosis for visual recovery [32]. FA is useful in differentiating active from inactive uveitis and also to confirm a CME diagnosis, choroidal neovascularization, and subtle retinal vasculitis, to monitor response to therapy, and to identify areas of capillary non-perfusion and retinal neovascularization. The small molecules of free, unbound fluorescein dye leak out even from minimally inflamed retinal vessels [135]. The characteristic appearance in eyes with uveitic CME is a “petaloid” pattern of parafoveal hyperfluorescence [135]. CME has been angiographically graded as [136] Grade 0, no sign of fluorescein leakage; Grade I, slight fluorescein leakage into cystic spaces but not enough to enclose the entire fovea centralis; Grade II, complete circular accumulation of the fluorescein in the cystic space but its diameter is smaller than 2 mm; and Grade III, the circular accumulation of fluorescein is larger than 2.0 mm in diameter. There have been attempts to describe OCT anatomical characteristics that can identify CME of different etiologies. Microfoci, thought to be caused by lipid-rich and lipoprotein-rich deposits or lipid-laden macrophages [16], were found to be one such differentiating characteristic on OCT [137]. These foci are characteristic for DME and RVO, although they differ in location and presentation according to the underlying disease [16, 138]. Munk et al. reported that microfoci were found in 100 % of CME eyes with CRVO, in 98 % of the eyes with DME, and in 65 % of eyes with BRVO, but in no eye with pseudophakic CME or uveitic CME [137]. IRF accumulation occurs in CME irrespective of the disease entities and differences in morphologic and spatial presentation, although previous histologic reports indicate that IRF may vary according to its underlying pathology [26, 139, 140]. Posterior uveitis is accompanied by choroidal thickening especially in an acute phase [141, 142]. With this technique, macular choroidal changes in eyes with anterior and intermediate uveitis are less marked compared to posterior uveitis and panuveitis [143]. CME is related to the use of drugs like prostaglandin analogues, epinephrine and epinephrine-like drugs, nicotinic acid, pioglitazone, rosiglitazone, docetaxel, and paclitaxel presumably by inducing an inflammatory reaction that causes breakdown of the blood retinal barrier and can also be monitored using OCT [144–149].

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Role of Fundus Autofluorescence Imaging in CME Fundus autofluorescence (FAF) is determined by the lipofuscin distribution in the RPE and is also influenced by macular pigments in the INL, ONL, and OPL [150, 151]. RPE autofluorescence depends on outer segment renewal and can be affected by the RPE’s ability to clear lipofuscin. Lipofuscin accumulation leads to reduced RPE phagocytic capacity which in turn can lead to RPE cell death and photoreceptor loss. Increased FAF is seen with RPE dysfunction and decreased FAF with loss of photoreceptors or the RPE [152]. CME is associated with increased FAF, thought to be due to macular neurosensory retinal tissue stretching that displaces macular pigments laterally thereby reducing the density of macular pigments, which increases the autofluorescence signal (Fig. 10) [153–155]. In eyes with CME, there have been attempts to correlate FAF with OCT parameters and VA and to predict restoration of photoreceptor integrity and subsequent visual recovery [156]. In DME, increased FAF is caused by the accumulation of oxidative products induced by activated microglia resulting in lipofuscin accumulation [157]. It has also been suggested that increased FAF in DME is not abnormal FAF. Rather, RPE autofluorescence is observed through a defect in the xanthophyll pigment [155]. At the foveola, blue-light FAF is very weak or almost absent in normal eyes because lutein and zeaxanthin are especially dense in the axons of the cone photoreceptors (Henle’s fiber) at the foveola and absorb the incident blue light. Increased foveolar FAF in DME has been shown to be associated with low ONL thickness, larger ellipsoid layer defect, and poor vision [156]. Hyper-FAF has been associated with functional and structural macular impairment in DME; [156] FAF decreases with DME resolution [157]. VA in eyes with DME and increased FAF is worse than that in eyes without increased FAF [155]. However FAF correlates better with OCT patterns and central field microperimetry than with VA [157]. FAF changes are not uniform in all patients with DME. Chung el al. reported that not all patients with a significant DME had comparable levels of increased FAF, nor did all patients with improved DME exhibit a significant decrease in FAF [156]. Functional improvement after DME treatment can be quantified on FAF and correlated with OCT morphology, thereby demonstrating a role for FAF as a prognostic factor in DME. Increased foveolar and perifoveolar petaloid FAF has been shown in uveitic CME (Fig. 15) [158, 159]. In some studies, however, the detection of pathologic FAF in patients with angiographically proven CME was only achieved in half the eyes, a limitation of FAF as compared to OCT [158]. Roesel et al. [158] focused on the correlation of FAF and OCT with visual acuity in eyes with uveitic CME. This group observed increased FAF and proposed that it arose from proteins such as retinoids in the extracellular fluid. Increased central FAF, the presence of cystoid changes, a disrupted ellipsoid layer, and ERM were associated with poor visual acuity. The FAF pattern found in uveitic CME may also reflect size, number, or fluorophore content of damaged RPE cells. Increased FAF has not been shown to be prominent in the diffuse type of uveitic CME [152]. There have also been attempts to classify abnormal FAF in CME with three main patterns described: cystoid hyperFAF, single or multiple spot hyper-FAF, and irregular hypo-FAF [160].

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En Face C-Scan Imaging in CME En face imaging or C-scan OCT produces frontal sections of the retinal layers and can be used to highlight specific aspects of CME. Creating an en face section at the ILM will show ERM and macular surface alterations. A scan about 40 μm deeper will show INL cystoid cells and an even deeper scan will show ONL cystoid cells [161]. En face OCT scans 40 μm beneath and parallel to the ILM show petal-shaped central and peripheral cavities. Deeper en face scans in the ONL show ovoid polygonal flower-shaped cystoid cells converging toward the fovea. In cases with advanced CME, the cells merge vertically first, and cells in the INL grow toward the ONL forming large vertically ovoid cavities. In CME a reduced intensity in the inner and outer segment en face image in areas with increased retinal thickness has been shown [162]. En face OCT cannot, however, determine the exact extent of CME because of the different layer location of the cysts [163, 164].

Further Advances in Imaging CME Several technologies are currently under development that could help visualize CME better. Already integrated in some platforms, Doppler OCT can measure blood flow in the retinal and choroidal vessels [165]. Swept-source OCT can achieve ultrahigh axial resolution by sweeping a narrow bandwidth light source through a broad optical range [166]. High-penetration posterior OCT (HP OCT) systems, which use a longer wavelength than standard penetration OCT (1060 vs. 830 nm), have higher choroidal penetration [167] allowing for better assessment of choroidal changes in CME. Adaptive optics (AO) scanning laser ophthalmoscopy has been used to document microcystic macular edema from en face images in patients with autosomal-dominant optic atrophy [168]. On AO, after BRVO-associated CME resolution, there is decreased parafoveal cone density and disruption of the cone mosaic spatial arrangement [169]. Swelling of Müller cells due to disturbed fluid transport has been described in eyes with macular edema [170–172]. Ultrahigh resolution OCT has been combined with AO to increase image resolution and to demonstrate morphological changes of Müller cells, which could unveil new information on the pathogenesis of CME. Other emerging technologies include optical coherence microangiography [173], phase variance imaging [174], and power or variance Doppler techniques [175] for noninvasive capillary level detection of the retinal vasculature. However the ability to acquire en face images of distinct capillary beds with current FA and OCT technology is limited. Prototype speckle variance OCT has been used for noninvasive real-time imaging the human retinal vasculature. This is complementary to FA and may provide superior capillary detail [176]. This method has the potential to noninvasively identify important pathological manifestations of CME [177]. Scattering OCT has the potential to visualize the choroidal vasculature of the macula and the optic nerve head without intravenous dye injection [166, 178].

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Retromode scanning laser ophthalmoscopy (SLO) has been used to visualize cystoid spaces in DME without the appearance of a shadow to the silhouetted cystoid space due to light scattering [179, 180]. Retromode SLO showed good agreement with OCT, FA, and FAF in identifying both honeycomb and petaloid patterns of DME [179]. Cysts of different dimensions were comparable to FA and the extent of DME correlated with retinal sensitivity [179, 181]. The application of OCT to image CME in the pediatric retina is also promising. CME in very preterm infants usually manifests as cystoid structures in the INL and rarely involves the other retinal layers [182]. CME in very preterm infants screened for retinopathy of prematurity is a developmental biomarker associated with decreased language and motor skills at 18–24 months corrected age [183].

Conclusion OCT, fluorescein angiography, and fundus autofluorescence have been demonstrated to be effective modalities to evaluate CME. While OCT allows evaluation of the location, extension, pattern, and microstructural anatomical features, FA allows identification of areas of leakage, thus providing complimentary yet distinct information for diagnosis of CME and monitoring its response to treatment. Future advances in imaging technology with higher acquisition speed and hardware motion tracking along with improved automated image segmentation analysis protocols will allow us to better characterize CME. Development of novel anatomical biomarkers can offer prognostic implications and monitor response to treatment. Newer imaging technologies including noninvasive OCT angiography hold promise to help better elucidate the pathology of CME. Conflict of Interest Disclosures Dr. Jaffe is a consultant to Heidelberg Engineering. Dr. Grewal does not have any financial or proprietary interests in this manuscript. Grant Support: Heed Ophthalmic Foundation, San Francisco, CA (DSG).

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107. Koizumi H, Spaide RF, Fisher YL, Freund KB, Klancnik Jr JM, et al. Three-dimensional evaluation of vitreomacular traction and epiretinal membrane using spectral-domain optical coherence tomography. Am J Ophthalmol. 2008;145:509–17. 108. Sonmez K, Capone Jr A, Trese MT, Williams GA. Vitreomacular traction syndrome: impact of anatomical configuration on anatomical and visual outcomes. Retina. 2008;28:1207–14. 109. Yamada N, Kishi S. Tomographic features and surgical outcomes of vitreomacular traction syndrome. Am J Ophthalmol. 2005;139:112–7. 110. Hassenstein A, Bialasiewicz AA, Richard G. Optical coherence tomography in uveitis patients. Am J Ophthalmol. 2000;130:669–70. 111. Markomichelakis NN, Halkiadakis I, Pantelia E, Peponis V, Patelis A, et al. Patterns of macular edema in patients with uveitis: qualitative and quantitative assessment using optical coherence tomography. Ophthalmology. 2004;111:946–53. 112. Iannetti L, Accorinti M, Liverani M, Caggiano C, Abdulaziz R, et al. Optical coherence tomography for classification and clinical evaluation of macular edema in patients with uveitis. Ocul Immunol Inflamm. 2008;16:155–60. 113. Estafanous MF, Lowder CY, Kaiser PK. Patterns of macular edema in uveitis patients. Ophthalmology. 2005;112:360; author reply 360–1. 114. Sivaprasad S, Ikeji F, Xing W, Lightman S. Tomographic assessment of therapeutic response to uveitic macular oedema. Clin Experiment Ophthalmol. 2007;35:719–23. 115. Castellano CG, Stinnett SS, Mettu PS, McCallum RM, Jaffe GJ. Retinal thickening in iridocyclitis. Am J Ophthalmol. 2009;148:341–9. 116. Moreno-Arrones JP, Gorrono-Echebarria MB, Teus-Guezala MA. Macular thickening in acute anterior uveitis with a 6-month remission period. Can J Ophthalmol. 2010;45:91–2. 117. Al-Mezaine HS, Al-Muammar A, Kangave D, Abu El-Asrar AM. Clinical and optical coherence tomographic findings and outcome of treatment in patients with presumed tuberculous uveitis. Int Ophthalmol. 2008;28:413–23. 118. Iannetti L, Spinucci G, Abbouda A, De Geronimo D, Tortorella P, et al. Spectral-domain optical coherence tomography in uveitic macular edema: morphological features and prognostic factors. Ophthalmologica. 2012;228:13–8. 119. Roesel M, Heimes B, Heinz C, Henschel A, Spital G, et al. Comparison of retinal thickness and fundus-related microperimetry with visual acuity in uveitic macular oedema. Acta Ophthalmol. 2011;89:533–7. 120. Belair ML, Kim SJ, Thorne JE, Dunn JP, Kedhar SR, et al. Incidence of cystoid macular edema after cataract surgery in patients with and without uveitis using optical coherence tomography. Am J Ophthalmol. 2009;148(128–135):e122. 121. Faia LJ, Sen HN, Li Z, Yeh S, Wroblewski KJ, et al. Treatment of inflammatory macular edema with humanized anti-CD11a antibody therapy. Invest Ophthalmol Vis Sci. 2011;52:6919–24. 122. Androudi S, Tsironi E, Kalogeropoulos C, Theodoridou A, Brazitikos P. Intravitreal adalimumab for refractory uveitis-related macular edema. Ophthalmology. 2010;117:1612–6. 123. Lehpamer B, Moshier E, Goldberg N, Ackert J, Godbold J, et al. Subretinal fluid in uveitic macular edema: effect on vision and response to therapy. Am J Ophthalmol. 2013;155:143–9. 124. Markomichelakis NN, Halkiadakis I, Pantelia E, Georgalas I, Chrysanthi K, et al. Course of macular edema in uveitis under medical treatment. Ocul Immunol Inflamm. 2007;15:71–9. 125. Munk MR, Kiss CG, Ekmekcioglu C, Huf W, Sulzbacher F, et al. Influence of orthostasis and daytime on retinal thickness in uveitis-associated cystoid macular edema. Curr Eye Res. 2014;39:395–402. 126. Ducos de Lahitte G, Terrada C, Tran TH, Cassoux N, LeHoang P, et al. Maculopathy in uveitis of juvenile idiopathic arthritis: an optical coherence tomography study. Br J Ophthalmol. 2008;92:64–9. 127. Kalinina Ayuso V, Makhotkina N, van Tent-Hoeve M, de Groot-Mijnes JD, Wulffraat NM, et al. Pathogenesis of juvenile idiopathic arthritis associated uveitis: the known and unknown. Surv Ophthalmol. 2014;59:517–31.

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128. de Boer J, Steijaert A, van den Bor R, Stellato R, Ossewaarde-van Norel J. Development of macular edema and impact on visual acuity in uveitis associated with juvenile idiopathic arthritis. Ocul Immunol Inflamm. 2015;23:67–73. 129. Sugar EA, Jabs DA, Altaweel MM, Lightman S, Acharya N, et al. Identifying a clinically meaningful threshold for change in uveitic macular edema evaluated by optical coherence tomography. Am J Ophthalmol. 2011;152(1044–1052):e1045. 130. Kempen JH, Sugar EA, Jaffe GJ, Acharya NR, Dunn JP, et al. Fluorescein angiography versus optical coherence tomography for diagnosis of uveitic macular edema. Ophthalmology. 2013;120:1852–9. 131. Domalpally A, Altaweel MM, Kempen JH, Myers D, Davis JL, et al. Optical coherence tomography evaluation in the Multicenter Uveitis Steroid Treatment (MUST) trial. Ocul Immunol Inflamm. 2012;20:443–7. 132. Payne JF, Bruce BB, Lee LB, Yeh S. Logarithmic transformation of spectral-domain optical coherence tomography data in uveitis-associated macular edema. Invest Ophthalmol Vis Sci. 2011;52:8939–43. 133. Brar M, Yuson R, Kozak I, Mojana F, Cheng L, et al. Correlation between morphologic features on spectral-domain optical coherence tomography and angiographic leakage patterns in macular edema. Retina. 2010;30:383–9. 134. Tran TH, de Smet MD, Bodaghi B, Fardeau C, Cassoux N, et al. Uveitic macular oedema: correlation between optical coherence tomography patterns with visual acuity and fluorescein angiography. Br J Ophthalmol. 2008;92:922–7. 135. De Laey JJ. Fluorescein angiography in posterior uveitis. Int Ophthalmol Clin. 1995;35: 33–58. 136. Miyake K. Prevention of cystoid macular edema after lens extraction by topical indomethacin (I). A preliminary report. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1977;203: 81–8. 137. Munk MR, Sacu S, Huf W, Sulzbacher F, Mittermuller TJ, et al. Differential diagnosis of macular edema of different pathophysiologic origins by spectral domain optical coherence tomography. Retina. 2014;34:2218–32. 138. Ogino K, Murakami T, Tsujikawa A, Miyamoto K, Sakamoto A, et al. Characteristics of optical coherence tomographic hyperreflective foci in retinal vein occlusion. Retina. 2012;32: 77–85. 139. Tso MO. Animal modeling of cystoid macular edema. Surv Ophthalmol. 1984;28(Suppl): 512–9. 140. Ossewaarde-van Norel J, Berg EM, Sijssens KM, Rothova A. Subfoveal serous retinal detachment in patients with uveitic macular edema. Arch Ophthalmol. 2011;129:158–62. 141. Nakayama M, Keino H, Okada AA, Watanabe T, Taki W, et al. Enhanced depth imaging optical coherence tomography of the choroid in Vogt-Koyanagi-Harada disease. Retina. 2012;32: 2061–9. 142. Kim M, Kim H, Kwon HJ, Kim SS, Koh HJ, et al. Choroidal thickness in Behcet's uveitis: an enhanced depth imaging-optical coherence tomography and its association with angiographic changes. Invest Ophthalmol Vis Sci. 2013;54:6033–9. 143. Gehl Z, Kulcsar K, Kiss HJ, Nemeth J, Maneschg OA, et al. Retinal and choroidal thickness measurements using spectral domain optical coherence tomography in anterior and intermediate uveitis. BMC Ophthalmol. 2014;14:103. 144. Moroi SE, Gottfredsdottir MS, Schteingart MT, Elner SG, Lee CM, et al. Cystoid macular edema associated with latanoprost therapy in a case series of patients with glaucoma and ocular hypertension. Ophthalmology. 1999;106:1024–9. 145. Telander DG, Sarraf D. Cystoid macular edema with docetaxel chemotherapy and the fluid retention syndrome. Semin Ophthalmol. 2007;22:151–3. 146. Modi D, Dubovy SR. Non-leaking cystoid maculopathy secondary to systemic paclitaxel. Ophthalmic Surg Lasers Imaging Retina. 2013;44:183–6. 147. Koo NK, Kim YC. A case of paclitaxel-induced maculopathy treated with methazolamide. Korean J Ophthalmol. 2012;26:394–7.

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148. Joshi MM, Garretson BR. Paclitaxel maculopathy. Arch Ophthalmol. 2007;125:709–10. 149. Ryan Jr EH, Han DP, Ramsay RC, Cantrill HL, Bennett SR, et al. Diabetic macular edema associated with glitazone use. Retina. 2006;26:562–70. 150. Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF. Fundus autofluorescence imaging: review and perspectives. Retina. 2008;28:385–409. 151. Trieschmann M, van Kuijk FJ, Alexander R, Hermans P, Luthert P, et al. Macular pigment in the human retina: histological evaluation of localization and distribution. Eye (Lond). 2008;22: 132–7. 152. Meleth AD, Sen HN. Use of fundus autofluorescence in the diagnosis and management of uveitis. Int Ophthalmol Clin. 2012;52:45–54. 153. McBain VA, Forrester JV, Lois N. Fundus autofluorescence in the diagnosis of cystoid macular oedema. Br J Ophthalmol. 2008;92:946–9. 154. Bessho K, Gomi F, Harino S, Sawa M, Sayanagi K, et al. Macular autofluorescence in eyes with cystoid macula edema, detected with 488 nm-excitation but not with 580 nm-excitation. Graefes Arch Clin Exp Ophthalmol. 2009;247:729–34. 155. Pece A, Isola V, Holz F, Milani P, Brancato R. Autofluorescence imaging of cystoid macular edema in diabetic retinopathy. Ophthalmologica. 2010;224:230–5. 156. Chung H, Park B, Shin HJ, Kim HC. Correlation of fundus autofluorescence with spectraldomain optical coherence tomography and vision in diabetic macular edema. Ophthalmology. 2012;119:1056–65. 157. Vujosevic S, Casciano M, Pilotto E, Boccassini B, Varano M, et al. Diabetic macular edema: fundus autofluorescence and functional correlations. Invest Ophthalmol Vis Sci. 2011;52: 442–8. 158. Roesel M, Henschel A, Heinz C, Dietzel M, Spital G, et al. Fundus autofluorescence and spectral domain optical coherence tomography in uveitic macular edema. Graefes Arch Clin Exp Ophthalmol. 2009;247:1685–9. 159. Bindewald A, Jorzik JJ, Roth F, Holz FG. cSLO digital fundus autofluorescence imaging. Ophthalmologe. 2005;102:259–64. 160. Shen Y, Xu X, Liu K. Fundus autofluorescence characteristics in patients with diabetic macular edema. Chin Med J (Engl). 2014;127:1423–8. 161. Lumbroso B, Huang D, Romano A, Rispoli M, Coscas G. Clinical en face OCT atlas. New Delhi: Jaypee Brother Medical Publishers; 2013. 162. Wanek J, Zelkha R, Lim JI, Shahidi M. Feasibility of a method for en face imaging of photoreceptor cell integrity. Am J Ophthalmol. 2011;152(807–814):e801. 163. Ohkoshi K, Tsuiki E, Kitaoka T, Yamaguchi T. Visualization of subthreshold micropulse diode laser photocoagulation by scanning laser ophthalmoscopy in the retro mode. Am J Ophthalmol. 2010;150:856–62. 164. Yamamoto M, Mizukami S, Tsujikawa A, Miyoshi N, Yoshimura N. Visualization of cystoid macular oedema using a scanning laser ophthalmoscope in the retro-mode. Clin Experiment Ophthalmol. 2010;38:27–36. 165. Michaely R, Bachmann AH, Villiger ML, Blatter C, Lasser T, et al. Vectorial reconstruction of retinal blood flow in three dimensions measured with high resolution resonant Doppler Fourier domain optical coherence tomography. J Biomed Opt. 2007;12: 041213. 166. Yasuno Y, Hong Y, Makita S, Yamanari M, Akiba M, et al. In vivo high-contrast imaging of deep posterior eye by 1-microm swept source optical coherence tomography and scattering optical coherence angiography. Opt Express. 2007;15:6121–39. 167. Povazay B, Hermann B, Unterhuber A, Hofer B, Sattmann H, et al. Three-dimensional optical coherence tomography at 1050 nm versus 800 nm in retinal pathologies: enhanced performance and choroidal penetration in cataract patients. J Biomed Opt. 2007;12: 041211. 168. Gocho K, Kikuchi S, Kabuto T, Kameya S, Shinoda K, et al. High-resolution en face images of microcystic macular edema in patients with autosomal dominant optic atrophy. Biomed Res Int. 2013;2013:676803.

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169. Akagi-Kurashige Y, Tsujikawa A, Ooto S, Makiyama Y, Muraoka Y, et al. Retinal microstructural changes in eyes with resolved branch retinal vein occlusion: an adaptive optics scanning laser ophthalmoscopy study. Am J Ophthalmol. 2014;157(1239–1249):e1233. 170. Scholl S, Kirchhof J, Augustin AJ. Pathophysiology of macular edema. Ophthalmologica. 2010;224 Suppl 1:8–15. 171. Augustin A, Loewenstein A, Kuppermann BD. Macular edema. General pathophysiology. Dev Ophthalmol. 2010;47:10–26. 172. Reichenbach A, Wurm A, Pannicke T, Iandiev I, Wiedemann P, et al. Muller cells as players in retinal degeneration and edema. Graefes Arch Clin Exp Ophthalmol. 2007;245:627–36. 173. Wang RK. Optical microangiography: a label free 3D imaging technology to visualize and quantify blood circulations within tissue beds in vivo. IEEE J Sel Top Quantum Electron. 2010;16:545–54. 174. Kim DY, Fingler J, Werner JS, Schwartz DM, Fraser SE, et al. In vivo volumetric imaging of human retinal circulation with phase-variance optical coherence tomography. Biomed Opt Express. 2011;2:1504–13. 175. Makita S, Hong Y, Yamanari M, Yatagai T, Yasuno Y. Optical coherence angiography. Opt Express. 2006;14:7821–40. 176. Xu J, Han S, Balaratnasingam C, Mammo Z, Wong KS, et al. Retinal angiography with realtime speckle variance optical coherence tomography. Br J Ophthalmol. 2015;99(10): 1315–9. 177. Hendargo HC, Estrada R, Chiu SJ, Tomasi C, Farsiu S, et al. Automated non-rigid registration and mosaicing for robust imaging of distinct retinal capillary beds using speckle variance optical coherence tomography. Biomed Opt Express. 2013;4:803–21. 178. Hong Y, Makita S, Yamanari M, Miura M, Kim S, et al. Three-dimensional visualization of choroidal vessels by using standard and ultra-high resolution scattering optical coherence angiography. Opt Express. 2007;15:7538–50. 179. Vujosevic S, Trento B, Bottega E, Urban F, Pilotto E, et al. Scanning laser ophthalmoscopy in the retromode in diabetic macular oedema. Acta Ophthalmol. 2012;90:e374–80. 180. Vujosevic S, Pucci P, Daniele AR, Convento E, Pilotto E, et al. Extent of diabetic macular edema by scanning laser ophthalmoscope in the retromode and its functional correlations. Retina. 2014;34:2416–22. 181. Murakami T, Nishijima K, Sakamoto A, Ota M, Horii T, et al. Foveal cystoid spaces are associated with enlarged foveal avascular zone and microaneurysms in diabetic macular edema. Ophthalmology. 2011;118:359–67. 182. Maldonado RS, O'Connell R, Ascher SB, Sarin N, Freedman SF, et al. Spectral-domain optical coherence tomographic assessment of severity of cystoid macular edema in retinopathy of prematurity. Arch Ophthalmol. 2012;130:569–78. 183. Rothman AL, Tran-Viet D, Gustafson KE, Goldstein RF, Maguire MG, et al. Poorer neurodevelopmental outcomes associated with cystoid macular edema identified in preterm infants in the intensive care nursery. Ophthalmology. 2015;122:610–9.

Part II

Medical Management of CME

Chapter 4

Medical Management of CME Associated with Uveitis Sarah M. Escott and Debra A. Goldstein

Introduction Cystoid macular edema (CME) develops following disruption to the blood-retinal barrier (BRB) and is the most common cause of vision loss in patients with uveitis [1]. Intraocular inflammation causes cellular damage resulting in activation of the arachidonic acid cascade and release of prostaglandins (PGE), nitric oxide (NO), interleukin 6 (IL-6), and vascular endothelial growth factor (VEGF) [2, 3]. These inflammatory mediators have been identified in the aqueous humor of patients with active uveitis leading to a pathologic hyperpermeability of the retinal vessel walls and causing damage to the RPE, resulting in fluid and protein extravasation into the retinal interstitium [4, 5]. Smoking and coexistent vascular disease also play a role in the pathogenesis of inflammatory macular edema [4, 6, 7]. The overall reported prevalence of visual impairment associated with uveitic CME is 33–42 % and is influenced by the location, severity, and duration of retinal edema [1, 8, 9]. Uveitic macular edema does not correlate with degree of active inflammation and may be diagnosed in up to 29 % of patients despite an overall inactivity of their uveitis [10]. Vision loss resulting from CME is more commonly reported in cases of intermediate and panuveitis as compared to anterior uveitis [8]. Poor visual prognostic indicators include advanced age, prolonged duration of uveitis, prolonged presence of edema, enlarged foveal avascular zone, and incomplete vitreous detachment [11]. Visual improvement occurs more often when CME has been present for ≤12 months compared to longer than 24 months [12, 13]. Chronic edema can lead to permanent photoreceptor damage, retinal atrophy, and fibrosis, such that normal vision may not return even with resolution of edema [14]. Further, restoring normal retinal architecture, even without restoration of normal vision, has S.M. Escott, MD • D.A. Goldstein, MD ( ) Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA e-mail: [email protected] © Springer International Publishing Switzerland 2017 S. Schaal, H.J. Kaplan (eds.), Cystoid Macular Edema, DOI 10.1007/978-3-319-39766-5_4

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a better prognosis for maintaining visual acuity [8]. For these reasons, the presence of any amount of CME warrants treatment. Medical treatment options include nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, anti-VEGF agents, and systemic immunomodulatory therapies. Steroids can be given topically, orally, via periocular or intravitreal injection, and by administration of depot preparations. The use of carbonic anhydrase inhibitors and octreotide has been suggested, but are not routinely used to treat uveitic ME [15, 16].

Nonsteroidal Anti-inflammatory Medications Topical NSAIDs block cyclooxygenase enzymes and inhibit prostaglandin synthesis thereby reducing inflammation, and have been shown to be effective at reestablishing the blood-aqueous barrier [17]. While the use of topical nonsteroidal anti-inflammatory medications has been proven efficacious for pseudophakic macular edema following cataract extraction, its use in uveitic ME has been disappointing [18]. Although not available in the USA, 3 months of topical 0.5 % indomethacin (INDOM) was shown to statistically improve acute inflammatory ME related to uveitis as compared to placebo in a randomized prospective trial [19].

Corticosteroids Corticosteroids possess anti-inflammatory and antiangiogenic properties due to their ability to suppress the production of inflammatory mediators (IL-6, PGE, VEGF) in a dose-dependent manner making them a good therapeutic option; they have been the mainstay of treatment for decades. More importantly, they have been shown to stabilize the endothelial and RPE tight junctions [20]. During the acute phase of inflammation, corticosteroids are highly effective due to their quick onset of action; however, side effects limit their long-term use [21].

Topical Corticosteroids Most topical treatments are inadequate for posterior segment disease due to pharmacokinetic limitations [22]. Recently, however, data suggest that topical difluprednate 0.05 % (Durezol; Alcon Laboratories) may have superior intraocular penetration as compared to other topical steroids. In addition, it does not contain the preservative benzalkonium chloride, an agent known to cause immunoallergic reactions, disrupt tear film stability, and cause toxic effects to the corneal epithelium [23]. Its high potency and limited systemic absorption make it an attractive therapeutic

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option [24]. It has been FDA approved for the treatment of postoperative inflammation and pain as well as anterior uveitis [25, 26]. Slabaugh et al. demonstrated a dramatic improvement in uveitic CME with difluprednate as both monotherapy and an adjuvant to immunomodulatory therapy in children with uveitis and macular edema; however, its benefit must be weighed against the heightened risk of cataract development (38 %) and clinically significant intraocular pressure elevation in this age group [27, 28]. Peak intraocular pressures of more than 30 mmHg were demonstrated to occur in 20 % of all eyes treated with difluprednate in one study, with 80 % of children experiencing a rise of more than 15 mmHg [28]. These studies emphasize the unpredictable, rapid, and dramatic IOP response to difluprednate in patients with uveitis and the need for close monitoring of IOP at every visit, especially in children. There are currently no randomized controlled trials comparing the efficacy of topical difluprednate to other steroid therapies for the treatment of uveitic CME.

Systemic Corticosteroids Oral corticosteroids are indicated for the treatment of vision-threatening uveitis. Oral prednisone is most often used, starting at a dosage of 0.75–2 mg/kg/day until inflammation responds, and then tapered gradually [29]. High doses of systemic corticosteroids can achieve rapid anatomical recovery of CME; however, their longterm use is not recommended due to serious potential side effects including peptic ulceration, Cushing syndrome, adrenal suppression, aseptic necrosis of the hip, systemic hypertension, and hyperglycemia [21, 30]. The Standardization of Uveitis Nomenclature (SUN) Working group has recommended consideration of alternate therapy if intraocular inflammation cannot be controlled with less than 7.5–10 mg per day of oral prednisone, or its equivalent, by 3 months [31].

Periocular Corticosteroids Periocular injection of corticosteroids has the ability to deliver a high concentration of drug within close proximity to the macula, making it an effective treatment for uveitic CME [32]. These injections are a useful adjunct to systemic treatment for uveitis when persistent or refractory macular edema is present; however, the effects can be temporary and serial injections are often necessary [33, 34]. Posterior subtenon (PSTK) or orbital floor injections of 40 mg of triamcinolone acetonide are the most commonly used methods of administration [34–36]. The effect on active inflammation has been observed to occur within days, and improvement in CME occurs within weeks to months [35, 36]. Resolution of macular edema occurs in approximately 50 % of patients 1–3 months following a single periocular injection, and the effect can last between 3 and 7 months [33–35]. In patients whose edema

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does not respond to one injection, resolution of edema has been demonstrated in 50–78 % of patients following serial injections, suggesting that there is added benefit with repeated treatments [33, 34]. Periocular triamcinolone injections have also been proven effective at controlling inflammation and reducing uveitic CME in children. In one combined prospective study, all eyes experienced improvement in anterior chamber inflammation following a single injection; however, relapse occurred after a mean of 4 months in 50 % of eyes. Of those eyes with uveitic CME at the time of treatment, resolution of the edema was observed in 55 % of eyes [37]. Common complications from periocular injections include ptosis, elevated IOP, and cataract progression. Elevation of IOP >24 mmHg is reported to occur in 22–34 % of eyes following periocular steroid injection, with a progression to requiring glaucoma surgery in 0.9–2.4 % within a year. The incidence of cataract progression is between fifteen and twenty percent [38, 39]. In children, visually significant cataract developed in 21 % of eyes at 5 months in one series, and was more common in eyes with mild posterior subcapsular opacities at the time of injection [37]. Rare but potentially devastating complications of periocular injections include globe perforation, optic nerve injuries, retinal detachment, and vascular occlusion [34, 40].

Intravitreal Corticosteroids Intravitreal corticosteroids have been used to treat various types of macular edema. Because other corticosteroids disappear in the vitreal cavity within a few days, triamcinolone acetonide (TA), which is largely water insoluble, is most commonly administered [41]. One study demonstrated the elimination half-life following a single injection of triamcinolone (4 mg/0.1 ml) to be approximately 18.7 (+/- 5) days for nonvitrecomized eyes and 2.3 days for one vitrecomized eye [41]. Intravitreal TA leads to a better response in resolving inflammatory macular edema when compared to periocular administration; however, the benefits are also transient, and they carry similar rates of posterior subcapsular cataract and IOP elevation, with the added risk of endophthalmitis [42]. Studies suggest improvement in macular edema can be detected as early as 1 week, with a peak response in 4–6 weeks and duration of effect between 6 weeks and 6 months. Many patients require more than one injection, and similar improvements in visual acuity and inflammatory edema may be achieved with repeat injections [43–45]. The greatest improvement in visual acuity was achieved in patients less than 60 years of age and in eyes with CME present for less than 12 months duration in one series. CME present for longer than 24 months was associated with the least improvement in visual acuity, even with improvement in macular thickness on OCT [13]. Elevation of intraocular pressure >10 mmHg has been reported in 25–34 % of eyes at a mean duration of 4–5 weeks following intravitreal triamcinolone injection. Antiglaucoma treatment was necessary in nearly 50 % of eyes in two large case

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series with no eyes requiring filtration surgery [13, 45]. Kok et al. observed a more profound IOP effect in eyes of patients younger than 40 years [13]. Cataract development has been observed in 15–30 % of patients receiving intravitreal triamcinolone injections; the risk increases following repeated injections [45]. In addition to elevated IOP and cataract, intravitreal triamcinolone carries a 0.05–0.1 % risk of endophthalmitis [46, 47].

Intravitreal Corticosteroid Depot Preparations Implantable long-acting corticosteroid therapies allow for delivery of a higher concentration of medication to the posterior segment over a sustained period while avoiding systemic side effects. These are beneficial options for treating patients with moderate to severe disease and for whom systemic immunosuppression medications are contraindicated, intolerable, or not able to completely control inflammation.

Ozurdex Dexamethasone is five times more potent than triamcinolone acetonide and more hydrophilic, allowing for higher vitreous concentrations; however, the clinical utility of single intravitreal injection is limited due to its short half-life of only 3 h [48]. The biodegradable dexamethasone intravitreal implant (Ozurdex, Allergan) is designed to deliver 700 μg of preservative-free dexamethasone in a sustainedrelease manner over 3–6 months. The implant is made of a solid polymer which enables dual-phase pharmacokinetics, initially releasing a burst of dexamethasone to rapidly achieve a therapeutic concentration, followed by a slower sustained release [49]. The implant is administered as an office-based intravitreal injection using a 22-gauge injecting applicator through the pars plana under a sterile biplanar technique [49] (Fig. 1). The biodegradable design allows repeat implantation to be performed without need for surgical removal [9]. Ozudex was approved by the US FDA in 2010 as first-line therapy in the treatment of macular edema associated with noninfectious intermediate and posterior uveitis [50]. Drug diffusion and clearance from the vitreous cavity is more rapid in vitrectomized eyes; studies show the effect at 3 months is only maintained in a third of vitrectomized eyes which had improvement in CME at 1 month. Due to risk of migration into the anterior chamber and subsequent corneal decompensation, the implant should not be used in aphakic vitrectomized eyes [51]. A randomized clinical trial demonstrated excellent results in the reduction of vitreous haze for patients with noninfectious intermediate uveitis; however, the mean improvement in macular edema dissipated before 26 weeks, suggesting the need for reinjection to treat CME [52]. Other reports suggest the implant is effective at treating refractory uveitic ME refractory for a period of 3–4 months with most patients requiring repeat implants within 6 months for recurrent CME [51, 53].

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Fig. 1 Ozurdex implant imaged in the vitreous immediately following injection in a patient with multifocal choroiditis

Multiple implants were required in 63 % of eyes in one retrospective observational study of patients with active noninfectious uveitis, 91 % of which had CME, over a 17-month period [54]. The response to repeat Ozurdex implantation mirrors that seen after a single injection; improvement in visual acuity and macular edema is observed after 1 month. The effects of repeated injections have shown to be cumulative, with long-term improvement in best-corrected visual acuity and stabilization of central retinal thickness over 24 months [54]. Although studies suggest no statistically significant increase in the rate of cataract formation between treatment and sham patients following one dexamethasone implant [52], one study did report development of posterior subcapsular opacity following a third injection [54]. Lowder et al. described 30 mmHg, commonly occurring within the first year following implantation. Surgical intervention was required in one-third of patients based on uncontrolled

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IOP, visual field, or disk changes [60, 63, 64]. Baseline visual field testing and optic nerve imaging are therefore recommended for patients undergoing fluocinolone implant surgery [63]. The fluocinolone acetonide implant carries a nearly 100 % incidence of cataract progression [60, 64]. Studies have demonstrated the feasibility and success of combined cataract extraction with IOL insertion at the time of fluocinolone acetonide implantation [61]. Additional risks of implant surgery include vitreous hemorrhage, hyphema, retinal detachment, and endophthalmitis [61]. Spontaneous separation of the medication pellet from its attachment is a rare but potential complication that may require surgery [65–67]. Complications such as retinal commotio, retinal tear, and endothelial failure due to dislocation of the pellet into the anterior chamber have also been reported [66, 67].

Anti-vascular Endothelial Growth Factor Medications Vascular endothelial growth factor (VEGF) has been found in the aqueous humor of patients with uveitis and plays a role in the loss of vascular integrity which ultimately causes CME [4, 68, 69]. VEGF expression is induced by inflammatory mediators and cytokines which are produced and abundantly present in the eyes of patients with uveitis [4, 68]. Further, VEGF concentrations have been shown to be higher in patients who had CME associated with uveitis as compared to those without CME [69]. The use of intravitreal anti-VEGF therapies bevacizumab and ranibizumab has recently been described as off-label treatment for inflammatory CME; however, their effects in this setting are not well established and results have been inconsistent [12, 70–76]. Numerous studies have observed statistically significant decrease in central retina thickness on optical coherence tomography [71–74], while others report limited to no change [75, 76]. One reason for this may be that anti-VEGF agents have not been shown to display anti-inflammatory properties, and therefore, studies which included patients with active uveitis at the time of treatment may have underestimated their effect on CME [75, 76]. Mackensen et al. showed statistically significant reduction in macular thickness beginning as early as 2 weeks following a single bevacizumab injection for patients with controlled uveitis but breakthrough CME refractory to steroid therapies. These effects, however, were sustained for only 6–8 weeks, and repeat injections were required [73]. Lott et al. observed a 40 % worsening of vision and no improvement in central retinal thickness for eyes treated with intravitreal bevacizumab only; however, most of the patients in this series had active uveitis at the time of treatment [75]. Acharya et al. demonstrated a positive effect of monthly ranibizumab injection in eyes with controlled uveitis and persistent CME in a small prospective, noncomparative, interventional case series [71]. Improvement in macular edema occurred as early as 1 week and was maintained at 3 months in all eyes. Approximately 60 % of eyes required repeat injection, and these results were preserved 3 months after cessation of treatment [71].

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The ideal dosing and sequence for intravitreal anti-VEGF agents in the treatment of inflammatory CME has yet to be determined; however, their length of effect is shorter than for periocular or intravitreal steroid therapies [77]. These agents are much less likely to cause glaucoma or cataract progression compared to steroid therapies; however, serial injections (every 5 weeks) in patients with macular degeneration were shown to lead to sustained elevation of IOP in 3.5–4.5 % of patients following a mean of 20 injections [78]. Mild anterior uveitis has been reported as an adverse side effect following 0.14–1.57 % of bevacizumab injections and 1.38 % with ranibizumab [79, 80].

Intravitreal Methotrexate Methotrexate (MTX) is a folate antagonist designed to competitively inhibit dihydrofolate reductase which is required for cellular proliferation [81]. It has long been used as a systemic immunomodulatory therapy. MTX has been increasingly used to treat various ophthalmic conditions both locally and systemically. The off-label use of intravitreal methotrexate to treat uveitic cystoid macular edema was examined in a few small studies [82–84]. In one prospective case series, patients with unilateral active, noninfectious uveitis or inflammatory CME were given intravitreal injections of MTX (400 μg/0.1 ml). A rapid reduction in inflammation and macular thickness was observed within 1 week. Visual acuity improvement of at least two Snellen lines was achieved in 87 % of patients at 3 months. While the inflammation tended to relapse after 4 months, the reduction in macular thickness was maintained at 6 months in all patients where OCT was able to be performed [82]. Other reports have described promising results of intravitreal methotrexate on the control of uveitis with or without CME [84, 85]. One study describes its use for the treatment of refractory unilateral retinal vasculitis due to Behçet disease in patients intolerant of corticosteroids or in whom they were contraindicated [84]. Study eyes underwent monthly intravitreal injections of MTX until remission of intraocular inflammation and/or stable visual acuity was achieved. Increase in visual acuity by three or more Snellen lines was observed in 85 % of study eyes following an average of four injections. Intravitreal MTX therapy resulted in a decrease in aqueous humor levels of IL-6 and IL-8 in treatment eyes [84]. IL-6 has been associated with breakdown of the blood-retinal barrier in uveitic disease, while IL-8 is a mediator of the innate immune response and is thought to play a role in altered vascular permeability [86, 87]. Significant reduction in the levels of these cytokines was associated with clinical improvement in 87 % of eyes [84]. A larger, multicenter, international retrospective case series evaluated eyes with active uveitis or uveitic CME treated with intravitreal MTX. Following one injection, 79 % of eyes entered a period of remission averaging 17 months. Of those who relapsed after one injection, 87 % entered a period of extended remission following a second injection. There was an overall average reduction in macular thickness maintained over a range of 10–30 months. Half of the patients receiving oral corticosteroids at the

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time of TX injection were able to successfully reduce steroid doses following intravitreal MTX [85]. Based on limited available data, intravitreal MTX may be a reasonable and effective option for patients with active unilateral uveitis and/or inflammatory CME who are known steroid responders or those in whom an elevation of IOP could be immediately detrimental.

Subcutaneous Interferon Alpha Interferon alpha (IFN) is a cytokine belonging to the subgroup of type I interferons that exert strong antiviral, antiproliferative, and various immunomodulatory effects [88]. The interferons influence both innate and adaptive immune responses and have been successful at treating Behçet disease and multiple sclerosis [89]. They are approved for the treatment of viral hepatitis and myeloproliferative syndromes. In recent years, systemic interferon alpha has been reported to be very successful in the treatment of Behçet disease and other cases of refractory uveitis [90, 91]. Dueter et al. reported resolution of chronic macular edema in a small series of patients treated with systemic interferon-α. All patients had otherwise inactive uveitis with CME that had been persistent for an average of 36 months and had failed to respond to corticosteroids. All patients were treated with an initial dose of three to six million IU subcutaneously based on body weight which was tapered in a stepwise fashion. Stable complete remission of CME was achieved in more than half of patients [92]. Common side effects of interferons are dose dependent and include flu-like illness, nausea, fatigue, diarrhea, rash, anemia, elevated liver transaminases, leucopenia, alopecia, dermatitis, and mild depression [93]. Some patients will develop neutralizing antibodies which render them unresponsive to this treatment. Interferon therapy, like all other systemic therapies except the recently approved TNF inhibitor, adalimumab, has not been US FDA approved for the treatment of uveitis.

Antitumor Necrosis Factor Alpha Medications Tumor necrosis factor alpha (TNF α), one of the proinflammatory cytokines found to occur at high levels in eyes with uveitis, activates T cells and macrophages, thereby increasing the expression of endothelial adhesion molecules and other proinflammatory cytokines [94, 95]. Inhibition of TNF α provides an attractive opportunity for more targeted anti-inflammatory therapy. Murphy et al. were the first to demonstrate efficacy of TNF inhibition in the treatment of refractory noninfectious posterior uveitis [96]. Several case series have reported resolution of coexisting CME following TNF-alpha treatment for noninfectious uveitis; however, their use must be weighed against the risk of possible side

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effects [97–101]. TNF inhibitors are increasingly used for the therapy of posterior uveitis and retinal vasculitis, and more data will likely be available regarding their effects on uveitic macular edema. As well, other biologic therapies are being used in the treatment of uveitis, and data on their efficacy is gradually becoming available. Adalimumab received US FDA approval for the treatment of adults with noninfectious intermediate, posterior, or panuveitis in June, 2016, making it the first FDAapproved non-corticosteroid therapy for uveitis. Data regarding its effects on CME in patients in the registration trials is not yet available.

Choosing the Right Treatment The decision regarding how to approach the treatment of inflammatory CME should include a careful assessment of individual clinical factors. The first priority must always be to quiet the inflammation, followed by restoration of normal structural integrity. Therapy differs depending upon laterality, severity, coexisting conditions such as cataract and glaucoma, history of steroid response, systemic comorbidities, and patient age. Local therapy may be more appropriate for unilateral disease, while systemic medications are often favored for bilateral conditions. Pseudophakic patients with mild disease and normal intraocular pressure may be treated with topical or periocular steroids; phakic patients should be counseled on their risk of cataract progression. Refractory cases or those who develop a steroid response should be considered for alternate therapy. For patients with moderate to severe disease who would like to avoid systemic immunosuppression or in whom such therapy is contraindicated, steroid implants may be the preferred option. For patients on systemic therapy in whom intraocular inflammation is active at the time of CME diagnosis, adjustments to dosing or frequency of immunomodulatory therapy may be all that is required. In some patients, systemic therapy may need to be initiated. Care must be taken when treating children with steroid therapy. The risks of developing cataract and glaucoma with topical or local steroid therapy may be higher in children, and the significance of these diagnoses also carries more weight in children. Intraocular pressure and optic disk health must always be monitored in children with uveitis, especially those treated with steroid therapy. Alternative treatment measures should be sought if signs of glaucoma are observed. Finally, the clinician should also be alert to the presence of structural abnormalities such as vitreomacular traction, epiretinal membrane, and gliosis of the internal limiting membrane (ILM) which can contribute to chronic macular edema that is refractory to medical therapies and which may require surgery. Our expanding knowledge regarding the pathophysiology of uveitis and the advent of enhanced imaging modalities have improved our ability to diagnose and develop novel therapeutic approaches to manage inflammatory CME. Despite this, the treatment continues to be challenging. There is no single preferred approach, and therapy should be tailored to the individual. Early and aggressive treatment is recommended to give the best potential for visual recovery.

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79. Ladas ID, Karagiannis DA, Rouvas AA, Kotsolis AI, Liotsou A, Vergados I. Safety of repeat intravitreal injections of bevacizumab versus ranibizumab. Retina. 2009;29(3):313–8. 80. Fung AE, Rosenfeld PJ, Reichel E. The international l intravitreal bevacizumab safety survey: using the internet to assess drug safety worldwide. Br J Ophthalmol. 2006;90(11):1344–9. 81. Cronstein BN. The mechanism of action of methotrexate. Rheum Dis Clin North Am. 1997;23(4):739–55. 82. Taylor SR, Habot-Wilner Z, Pacheco P, Lightman SL. Intraocular methotrexate in the treatment of uveitis and uveitic cystoid macular edema. Ophthalmology. 2009;116(4):797–801. 83. Hardwig PW, Pulido JS, Erie JC, Baratz KH, Buettner H. Intraocular methotrexate in ocular diseases other than primary central nervous system lymphoma. Am J Ophthalmol. 2006;142(5):883–5. 84. Bea JH, Lee SC. Effect of intravitreal methotrexate and aqueous humor cytokine levels in refractory retinal vasculitis in Behcet disease. Retina. 2012;32(7):1395–402. 85. Taylor SRJ, Banker A, Schlaen A, Couto C, Matthe E, Joshi L, Menezo V, Nguyen E, Tokinsnetzer O, Bar A, Morarji J, McCluskey P, Lightman S. Intraocular methotrexate can induce extended remission in some patients in noninfectious uveitis. Retina. 2013;33(10):2149–54. 86. Hoekzema R, Verhagen C, van Haren M, Kijlstra A. Endotoxin-induced uveitis in the rat. The significance of interleukin-6. Invest Ophthalmol Vis Sci. 1992;33(3):532–9. 87. Yoshida A, Yoshida S, Khalil AK, et al. Role of NF-kappaB mediated interleukin-8 expression in intraocular neovascularization. Invest Ophthalmol Vis Sci. 1998;39(7):1097–106. 88. Dueter CM, Koetter I, Guenaydin I, Stuebiger N, Zierhut M. Interferon alfa-2a: a new treatment option for long lasting refractory cystoid macular edema in uveitis? A pilot study. Retina. 2006;26(7):786–91. 89. Mackensen F, Max R, Becker MD. Interferons and their potential in the treatment of ocular inflammation. Clin Ophthalmol. 2009;3:559–66. 90. Bodaghi B, Gendron G, Wechsler TC, Cassoux N, du Huong LT, Lemitre C, Fradeau C, LeHoang P, Piette JC. Efficacy of interferon alpha in the treatment of refractory and sight threatening uveitis: a retrospective monocentric study of 45 patients. Br J Ophthalmol. 2007;91(3): 335–9. 91. Kotter I, Zierhut M, Eckstein AK, Vonthein R, Ness T, Gunaydin I, Grimbacher B, Blaschke S, Meyer-Riemann W, Peter HH, Stubiger N. Human recombinant interferon alpha-2a for the treatment of Behcet’s disease with sight threatening posterior or panuveitis. Br J Ophthalmol. 2003;87(4):423–31. 92. Deuter CM, Kotter I, Gunaydin I, Stubiger N, Doycheva DG, Zierhut M. Efficacy and tolerability of interferon alpha treatment in patients with chronic cystoid macular edema due to noninfectious uveitis. Br J Ophthalmol. 2009;93(7):906–13. 93. Sleijfer S, Bannink M, Van Gool AR, Kruit WH, Stoter G. Side effects of interferon-alpha therapy. Pharm World Sci. 2005;27(6):423–31. 94. Dick AD, Forrester JV, Liversidge J, Cope AP. The role of tumor necrosis factor (TNF-alpha) in experimental autoimmune uveoretinitis (EAU). Prog Retin Eye Res. 2004;23(6):617–37. 95. Santos LM, Marcos MC, Gallardo GJM, Gomez VMA, Collantes EE, Ramirez CR, Omar M. Aqueous humor and serum tumor necrosis factor-alpha in clinical uveitis. Ophthalmic Res. 2001;33(5):251–5. 96. Murphy CC, Ayliffe WH, Booth A, Makanjuola D, Andrews PA, Jayne D. Tumor necrosis factor alpha blockage with infliximab for refractory uveitis and scleritis. Ophthalmology. 2004;111(2):352–6. 97. Murphy CC, Greiner K, Plskova J, Duncan L, Frost A, Isaacs JD, REbello P, Waldmann H, Hale G, Forrester JV, Dick AD. Neutralizing tumor necrosis factor activity leads to remission in patients with refractor noninfectious posterior uveitis. Arch Ophthalmol. 2004;122(6):845–51. 98. Markomichelakis NN, Theodossiadis PG, Pantelia E, Papaefthimiou S, Theodossiadis GP, Sfikakis PP. Infliximab for chronic cystoid macular edema associated with uveitis. Am J Ophthalmol. 2004;138(4):648–50.

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99. Erckens RJ, MOstard RL, Wijnen PA, Schouten JS, Drent M. Adalimumab successful in sarcoidosis patients with refractory chronic noninfectious uveitis. Graefes Arch Clin Exp Ophthalmol. 2012;250(5):713–20. 100. Hale S, LIghtman S. Anti-TNF therapies in the management of acute and chronic uveitis. Cytokine. 2006;33(4):231–7. 101. Schaap-Fogler M, Amer R, Friling R, Priel E, Kramer M. Anti-TNF agents for refractory cystoid macular edema associated with noninfectious uveitis. Graefes Arch Clin Exp Ophthalmol. 2014;252(4):633–40.

Chapter 5

Medical Management of CME Associated with Diabetes Reid Turner and Lucian V. Del Priore

Introduction The World Health Organization reported in 2010 that the world prevalence of diabetes among adults aged 20–79 was 6.5 %, affecting over 285 million people [1]. This number is predicted to rise to over 400 million adults in the year 2030 as average life expectancy increases and the obesity epidemic grows in developed nations. Diabetic retinopathy has important public health implications as it is the leading cause of blindness in working age adults. Since nearly all patients with type I diabetes and up to 60 % of patients with type II diabetes will develop diabetic retinopathy 20 years from initial diagnosis, it has been imperative to identify strategies to prevent and/or limit morbidity from diabetic retinopathy [2]. Diabetic macular edema (DME) is the most common cause of vision loss in patients with diabetes and affects nearly 75,000 new patients in the United States each year. The treatment of DME was investigated by the Early Treatment of Diabetic Retinopathy Study (ETDRS), which was a landmark randomized, controlled, multicenter clinical trial performed from 1979 to 1989 [3]. The ETDRS further defined “clinically significant” DME (CSDME) for the purpose of treatment guidelines as seeing at least one of the following on clinical examination: • Retinal thickening within 500 μm of the center of the fovea • Hard exudates within 500 μm of the center of the macula with adjacent retinal thickening • Retinal thickening at least 1 disk area in size, any part of which is within 1 disk diameter of the center of the macula R. Turner, MD Department of Ophthalmology, Medical University of South Carolina, Storm Eye Institute, 167 Ashley Avenue, 8th Floor, Charleston, SC 29425, USA L.V. Del Priore, MD, PhD (*) Department of Ophthalmology, Yale University School of Medicine, New Haven, CT, USA e-mail: [email protected] © Springer International Publishing Switzerland 2017 S. Schaal, H.J. Kaplan (eds.), Cystoid Macular Edema, DOI 10.1007/978-3-319-39766-5_5

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Of note, the diagnosis of CSDME has historically been determined by slit lamp biomicroscopy or stereographic photos and not with fluorescein angiography. Optical coherence tomography (OCT) has emerged as a valuable diagnostic tool that is more sensitive in detecting early DME by determining the thickness of the macular center or central subfield thickness [4]. Although CSDME may present without visual-acuity changes, up to 30 % of patients with CSDME will develop moderate visual loss, defined as a doubling of the visual angle. The ETDRS-established laser photocoagulation as the initial gold standard therapy for DME. Laser photocoagulation is effective in preventing further vision loss from DME, but is less successful in improving visual acuity. Since the ETDRS, a better understanding of the pathophysiology of DME has occurred allowing new treatment strategies to be developed. Anti-VEGF agents have emerged as the favored treatment of center-involving DME with roughly 90 % of retina specialists in 2013 in the United States reportedly using anti-VEGF agents as their initial therapy [5].

Pathophysiology of DME The pathophysiology of DME is a complex process caused by multiple factors which results in the breakdown of the blood-retina barrier (BRB). The BRB consists of an inner biological unit formed by tight junctional complexes between the retinal vascular endothelial cells and a network of glial cells, astrocytes, and Müller cells, to maintain a low permeability environment; the outer BRB is formed by tight junctions between the retinal pigment epithelium (RPE). Breakdown of the BRB leads to leakage of fluid, retinal thickening, and exudates that cause retinal dysfunction and vision loss [6]. Chronic hyperglycemia is generally accepted as the major pathological factor contributing to diabetic retinopathy and DME. Elevated blood glucose levels lead to increased intracellular levels of glucose which may then react with proteins, lipids, and nucleic acids to subsequently form advanced glycation end-products (AGEs). The receptor for AGEs is expressed on endothelial cells and is called RAGE. The binding of AGE to RAGE leads to endothelial dysfunction and breakdown of the BRB via oxidative stress, the release of proinflammatory cytokines, and increased expression of vascular endothelial growth factor-A (VEGF-A) [7]. VEGF-A was identified in 1983 as a 34–42 kDa protein that is able to induce significant vascular leakage. When compared to histamine on a molar basis, VEGF-A is estimated to be 50,000 times more effective at inducing vascular permeability. Fetal liver kinase-1 (FLK-1) is a tyrosine kinase receptor that has been identified as the principle mediator of VEGF-A’s effect on vascular permeability and angiogenesis. Elevated levels of VEGF-A in the vitreous and anterior chamber have been shown to correlate with the severity of DME, making it a key player in the pathogenesis of DME [8]. Additional vasoactive factors implicated in the pathogenesis of DME are protein kinase C (PKC) and angiotensin II (AII). PKC is a family of serine-threonine

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kinases which are upregulated in diabetic patients and has been shown to increase vascular permeability and decrease retinal blood flow by increasing the expression of endothelins. Endothelins interact with receptors on pericytes to cause intracellular calcium-mediated vasoconstriction of the retinal microvasculature. AII has been shown to directly stimulate the secretion of VEGF in endothelial cells. Therapies targeting PKC and AII have been shown to reduce the retinal vascular changes associated with diabetes in animal models [9]. There have been many more factors identified in the pathogenesis of DME. This has led to the evolution in the management of DME as targeted therapies have developed. Further understanding of the causes of BRB breakdown will undoubtedly lead to new treatments both locally and systemically for DME.

Medical Management of DME There are several effective treatment modalities for DME. Laser photocoagulation and surgical intervention will be covered in a later chapter. Current medical therapies include systemic risk factor modification, topical eye drops, and intravitreal injection of steroids and anti-VEGF agents. These treatments are summarized in Table 1.

Systemic Control [10, 11] The primary goals of systemic intervention are to prevent the development of diabetic retinopathy/DME and to reduce vision loss in patients with existing retinopathy/DME. The mainstays of systemic control are blood sugar and blood pressure control. More recently, therapies targeting the renin-angiotensin system (RAS) and lipid-lowering agents have been investigated. Improvement in systemic risk factors alone can significantly decrease the risk of vision loss from DME.

Glycemic Control The most effective systemic intervention to prevent the progression of diabetic retinopathy is improved glycemic control seen by a lowering of glycosylated hemoglobin (HbA1c). This was established by the Diabetes Control and Complications Trial (DCCT) in type 1 diabetics and the UK Prospective Diabetes Study (UKPDS) in type 2 diabetics. Both studies showed intensive glycemic control reduced the incidence and progression of diabetic retinopathy. Not surprisingly, intensive glycemic control is associated with an increased risk of hypoglycemic events. Additionally, the Action to Control Cardiovascular Risk in

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Table 1 Summary of medical therapies for DME Treatment Advantages/disadvantages Systemic risk factor modification Glycemic control Decreases morbidity from retinopathy, nephropathy, and neuropathy Increased risk of hypoglycemic events

Blood pressure control ReninAngiotensin System (RAS)

Decreased risk of heart attack

Lipid-lowering agents

Decreased risk of retinopathy progression, DME, and cardiovascular disease

Topical Therapy NSAID and steroid eye drops

Decreased risk of retinopathy progression

Low risk of treatment Ease of delivery Intravitreal Injection Anti-VEGF Greatest improvement in visual-acuity agents and anatomic outcomes Need for frequent visits and repeated treatments, risk of infection, unknown long-term systemic side effects Steroids Improvement in visual-acuity and anatomic outcomes May help cases poorly responsive to anti-VEGF Risk of cataract and glaucoma progression

Literature support Diabetes Control and Complications Trial (DCCT) UK Prospective Diabetes Study (UKPDS) Action to Control Cardiovascular Risk in Diabetes (ACCORD) Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) Diabetic Retinopathy Candesartan Trials (DIRECT) European Controlled Trial of Lisinopril in Insulin-Dependent Diabetes (EUCLID) Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Action to Control Cardiovascular Risk in Diabetes (ACCORD) Uncontrolled, retrospective studies

RESTORE study BOLT study VISTA-DME and VIVID-DME trials MEAD study BEVORDEX study Fluocinolone Acetonide for Diabetic Macular Edema (FAME) A and B studies

Diabetes (ACCORD) trial was stopped because an increase in all-cause mortality was identified in patients whose glucose was extremely tightly controlled with insulin and multiple oral agents. The validity of this association has been questioned, but nonetheless it is important to be cognizant of the potential risk. Optimal metabolic control in both type 1 and type 2 diabetics may be very difficult to achieve. Various interventions to improve patient education such as nurse education and group therapy sessions have been shown to improve HbA1c levels. Since diabetes is a chronic condition, it is imperative that patients have a thorough understanding of their illness which facilitates better compliance with medical therapies. The American Diabetes Association and the European Association for the Study of Diabetes provided a consensus statement in 2009 which provided guidance for a treatment algorithm for type 2 diabetes. The guidelines emphasized a goal HbA1c

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250 to 1,500 μm) The ERM may play an important role in chronic VMT syndrome [14, 20], mainly in broad adhesions (Fig. 3b) [21]. Partial PVD with vitreal traction can cause small splits within the ILM, allowing glial cells to gain access to the superficial retina (Fig. 2b). In these eyes, epiretinal fibroglial membranes proliferate from the retinal surface onto the back surface of the detached posterior vitreous face. This configuration imparts an increased strength of the vitreomacular adhesion and prolongs the duration of the VMT by preventing the spontaneous separation of the vitreous and the macula (Fig. 2b) [11, 13, 16]. Furthermore, the proliferative epiretinal fibroglial membranes contribute contractile forces by increasing the tangential traction via thickening and tightening of the detached posterior hyaloid and anchoring the

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posterior hyaloid to the surrounding retinal surface, thus enhancing the anteroposterior traction caused by the VMT adhesion [14, 20] (Fig. 6).

Macular Hole and Tractional Cystoid Macular Edema (Narrow VMT; Extension